HUT74006A - Hiv protease inhibitors in pharmaceutical combinations and pharmaceutical compns. contg. them - Google Patents

Abstract

Compounds of formula <CHEM> where R1 and R2 are independently hydrogen or optionally-substituted C1-4alkyl or aryl, or R1 and R2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors. These compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Description

* PHARMACEUTICAL COMBINATIONS OF CALLS FOR PROTEASE INHIBITORS SUITABLE FOR AIDS MANAGEMENT

The present invention relates to compounds that inhibit the protease encoded by the human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof. These are compounds that are useful in preventing, treating, and treating acquired immune deficiency syndrome (AIDS) caused by HIV infection. The present invention also relates to pharmaceutical compositions containing the above-mentioned compounds as active ingredients, and to methods of using these compounds and other agents in the treatment of viral infections caused by AIDS and HIV.

The Human Immunodeficiency Virus (HIV) designated retrovirus is a causative agent of complex diseases that include progressive destruction of the immune system (Acquired Immune Deficiency Syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-HI, or ARV. A common feature of retroviral replication is the extensive post-translational conversion of precursor polyproteins by a virally encoded protease to the mature viral protein required for virus construction and function. Inhibition of said transformation prevents the production of a normally infectious virus. For example, Kohl, N.E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988), have shown that genetic inactivation of the HIV-encoded protease results in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease is a viable method for the treatment of AIDS and the prevention of HIV infection

82358-2037 TEL / kov * or treatment. The HIV nucleotide sequence shows the presence of a pol gene in an open reading frame (Ratner, L., et al., Narure, 313, 277 (1985)). Amino acid sequence homology demonstrates that the pol sequence encodes a reverse transcriptase, an endonuclease and a HIV protease (Toh, H., et al., EMBO J., 4, 1267 (1985); Power, M.D. et al., Science, 231: 1567 (1986); Pearl, L.H. et al., Natur. 329, 351 (1987)]. The compounds of the present invention are HIV protease inhibitors.

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. These compounds may be used alone or in the form of a pharmaceutically acceptable salt thereof for the inhibition of HIV protease, for the treatment of HIV infection and for the treatment of AIDS, or as an active ingredient in a pharmaceutical composition optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. The invention further relates to a method for treating AIDS, a method for inhibiting HIV infection and a method for treating HIV infection.

The following abbreviations are used in our description:

abbreviations

Notation protecting group BOC (Boc) tert-butyloxy-carbonyl group CBZ (Cbz) benzyloxycarbonyl (carbobenzoxy) TBS (TBDMS) tert-butyl-dimethyl-silyl activation Group HBT (HOBT or HOBt) 1-hydroxybenzotriazole hydrate group coupling agent

BOP Reagent Benzo-triazyl-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate

BOP-C1

EDC (BOC) ₂ O (BOC ₂ O) n-Bu ₄ N + FnBuLi (n-Buli) DMF

Et ₃ N

EtOAc

TFA

DMAP

DME

LDA

THF

He

Val bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

Other di-tert-butyl dicarbonate tetrabutylammonium fluoride n-butyl lithium dimethylformamide triethylamine ethyl acetate trifluoroacetic acid dimethylaminopyridine dimethoxyethane lithium diisopropylamide tetrahydrofuran

Amino acid L-isoleucine L-valine.

FIELD OF THE INVENTION The present invention relates to compounds of Formula I, combinations thereof, and pharmaceutically acceptable salts thereof, for use in inhibiting HIV infection, preventing or treating HIV infection, and treating acquired immune deficiency syndrome (AIDS). Compounds of formula (I)

X is -OH or -NH ₂ ;

Z is -O, -S, or -NH;

R is hydrogen or C1-C4 alkyl;

R and R independently represent:

1) hydrogen,

2) C 1 -C 4 alkyl, unsubstituted or substituted with one or more of the following groups:

a) halogen,

b) a hydroxy group,

c) C 1-3 alkoxy,

d) an aryl group which is unsubstituted or substituted by one or more C 1-4 alkyl, hydroxy or aryl groups,

e) -W-aryl or -W-benzyl, wherein W is -O-, -S, or -NH-,

f) 5-7 membered cycloalkyl, unsubstituted or substituted with one or more of the following groups:

(i) halogen, (ii) hydroxy, (iii) C 1-3 alkoxy, or (iv) aryl,

g) a heterocyclic group which is unsubstituted or substituted with one or more C 1-4 alkyl groups optionally substituted with hydroxy groups or with Boc group,

SHE

h) -NH-CO (C1-C3 alkyl),

SHE

II

i) -NH-C- (C 1 -C 3) alkyl;

j) -NH-SO ₂ - (C 1 -C 3) alkyl;

k) -NR ₂ ,

l) -COOR or

m) - [(CH ₂ ) _in O] _n R wherein in is 2-5 and n is 0, 1, 2 or 3, or

3) an aryl group which is unsubstituted or substituted with one or more of the following groups:

a) halogen.

b) a hydroxy group,

c) -NO ₂ or -NR ₂ ,

d) C 1-4 alkyl;

e) C 1-3 -alkoxy, unsubstituted or substituted with one or more -OH or C 1-3 -alkoxy;

(f) -COOR,

SHE

II

g) -cnr ₂ ,

h) -CH ₂ NR ₂ ,

SHE

i) -CH ₂ NHCR,

j) -CN,

k) -cf ₃ , o

l) -NHCR,

m) aryl (C 1 -C 3 alkoxy);

n) aryl;

o) -NRSO ₂ R,

p) -OP (O) (OR _x ) ₂ or

q) -R ⁵ where R is as defined below; obsession

R ¹ and R * may be bonded to each other such that together with the nitrogen atom to which R ¹ is attached form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and C 2 to C 9 attached to R ¹ unsubstituted or substituted with the following groups:

1) a hydroxyl group,

2) C 1 -C 4 alkyl, unsubstituted or substituted with one or more of the following groups:

a) halogen,

b) a hydroxy group,

c) C 1-3 alkoxy,

d) an aryl group,

e) 5-7 membered cycloalkyl, unsubstituted or substituted with one or more of the following groups:

(i) halogen, (ii) hydroxy, (iii) C 1-3 alkoxy, or (iv) aryl,

(f) a heterocyclic group, or

3)

4)

5)

6)

7)

8)

-No ₂ ,

g) -No ₂ ,

C 1-3 alkoxy, O

II

-NH-CO (C 1-3 alkyl), O

-NH-C- (C 1 -C 3) alkyl,

-NH-SO ₂ - (C 1 -C 3) alkyl, heterocyclic,

-W-aryl, or

9) -W-C-aryl, wherein W is as defined above

O is the same; obsession

R ¹ and R 'may be linked to each other by a nitrogen atom

- to which R ¹ is attached - together form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and C 1 -C 8 attached to R 'and unsubstituted or substituted with the following groups:

1) N,

Io v R ¹ II wherein V is absent or is -CO- or -SO ₂ -Q-, where

R ¹ is as defined above for R ¹ independently of R ² and is not linked to R, and

Q is absent or represents a heterocyclic group substituted with -O-, -NR-, or optionally substituted with C 1 -C 4 alkyl,

2) -N- (heterocyclic) -,

3) -N- (C 1 -C 4 alkenyl) unsubstituted or substituted with aryl],

4) -N-

SO ₂ - (C 1 -C 4) alkenyl, unsubstituted or substituted with aryl,

5) -S (O) _p -, wherein p is 0, 1 or 2, or

6) -0-, or

R and R can be linked to each other by a nitrogen atom

- to which R ¹ is attached - together form a 3- to 10-membered monocyclic or bicyclic ring system containing a nitrogen atom and C 2 to C 9 attached to R ¹ , wherein the saturated ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with several of the following groups:

1) halogen,

2) C 1-3 alkoxy,

3) hydroxy,

4) C 1-4 alkyl;

5) -NHR where R is as defined above for R independently and is not linked to R; or

6) -NH- (heterocyclic) -,

R ³ represents

1) - (CH ₂ ) _r -R ⁴ where r is 0-5,

2) (C 1 -C 4 alkenyl) -R ⁴ , or

3) (C 1 -C 4 alkynyl) -R ⁴ ,

R ⁴ represents

1) hydrogen,

2) C 1-4 alkyl,

3) C 5-10 -cycloalkyl optionally substituted with hydroxy;

4) C 6 -C 10 aryl, unsubstituted or substituted with one or more of the following groups:

a) halogen,

b) a hydroxy group,

c) -NO ₂ or -NR ₂ ,

d) C 1-4 alkyl;

e) C 1-3 -alkoxy, unsubstituted or substituted with one or more -OH or C 1-3 -alkoxy;

(f) -COOR,

g) -cnr ₂ , o

h) -CH ₂ NR ₂ ,

SHE

i) -CH ₂ NHCR,

j) -CN,

k) -CF ₃ ,

SHE

l) -NHCR,

m) aryl (C 1-3 alkoxy),

n) aryl;

o) -NRSO ₂ R,

p) -OP (O) (OR _x ) ₂ or

q) -R ⁵ where R ⁵ is as defined below; obsession

5) a monocyclic or bicyclic heterocyclic group containing from 1 to 3 heteroatoms N, O or S and unsubstituted or substituted with R ⁵ and optionally one or more of the following:

a) halogen,

(b) C 1 -C 4 alkyl, or

c) C 1-3 alkoxy;

R _x is H or aryl;

R ⁵ represents

1) -W- (CH ₂ ) _m -NR ⁶ R ', wherein

W is as defined above, m is 2 to 5 and * R ⁶ and R ⁷ are independently

a) hydrogen

b) C 1-6 alkyl, unsubstituted or substituted with one or more of the following groups:

i) C 1-3 alkoxy, ii) -OH, or iii) -NR ₂ ,

c) R ⁶ and R ^{7 are the} same or different and are linked to one another

To form a 5- to 7-membered heterocyclic group, such as morpholino, and which may contain up to two further heteroatoms from the following groups:

R O

-N-, -O-, -S-, -S- or SO ₂ and the heterocyclic group is optionally substituted with C 1 -C 4 alkyl or

(d) an aromatic heterocyclic group which is unsubstituted or substituted with one or more of the following groups:

i) C 1-4 alkyl, or ii) -NR ₂ ,

2) - (CH ₂ ) _q -NR ⁶ R ⁷ wherein q is 1 -5 and R ⁶ and R are as defined above except that R ⁶ and R ⁷ are hydrogen or unsubstituted C 1 -C 6 other than alkyl, or

3) benzofuryl, indolyl, aza-cycloalkyl, azabicyclo (C 7 -C 11 cycloalkyl) or benzo-piperidinyl substituted with unsubstituted or C 1-4 alkyl;

Substituent B is absent or represents a group of formula (a) wherein

R ^K represents

1) -CH (CH ₃ ) ₂ ,

2) -CH (CH ₃ ) (CH ₂ CH ₃ ), or

3) phenyl;

J and J 'are independently

1) -YR ⁹ wherein

Y is -O- or -NH-, and

R ⁹ represents

a) a hydrogen atom,

b) C 1-6 alkyl, unsubstituted or substituted with one or more of the following groups:

(i) -NR ₂ , (ii) -OR, (iii) -NHSO ₂ - (C 1 -C 4) alkyl, (iv) -NHSO ₂ -aryl or -NHSO ₂ - (dialkylamino-aryl),

v) -CH ₂ OR, vi) C 1-4 alkyl,

SHE

II (vii) -COR,

SHE

II (viii) -CONR ₂ , ix) (b) or (c),

SHE

II

x) -NHCR ¹ wherein R ⁿ is

A) -H,

Β) C 1 -C 4 alkyl,

C) aryl;

D) heterocyclic group, or

Ε) -ΝΗ-, -Ο- or - (CH ₂ ) _n -, where η is 1, 2 or

3, and substituted with.

I) C 1-4 alkyl, unsubstituted or substituted with one or more aryl or heterocyclic groups, or

II) an aryl group which is unsubstituted or substituted with heterocycle, xi) -NR ₃ ', wherein A'jelentése a counterion, xii) -NR ¹⁰ R', wherein R ¹ and R ^{lc 11} are identical or different

C 1 -C 5 alkyl or together form a 5-7 membered heterocyclic group containing up to one further heteroatom selected from -O-, S- or -NR-, xiii) aryl, xiv) -CHO, xv) -OP (O) (OR _X ) ₂ ,

SHE

II xvi) -OC- (C 1 -C 4 alkyl) substituted with one or more amino groups or quaternary amino groups, or -O - [(CH ₂ ) _m O] _n -R, or -OP (O) ) (OR _X ) ₂ ),

O xvii) -OC-R, or

SHE

II xviii) -OC-NH-CH ₂ - (heterocyclic), or

c) - [(CH ₂ ) _m O] _n CH ₅ or - [(CH ₂ ) _m O] _n H where m and n are as defined above,

2) -N (R ⁹ ) ₂ ,

3) -NR ^{II R,} wherein R ⁰ and R ¹¹ are as defined above, or

4) a group of the formula d, wherein Y, R ⁹ and n are as defined above; and

R ¹² is as defined

1) hydrogen,

2) an aryl group optionally substituted with one or more of the following groups:

a) R ¹⁴ , wherein R ¹⁴ is

i) halogen, ii) -OR,

SHE

II iii) -CNR ₂ , arc) -CH ₂ NR ₂ ,

v) -SO ₂ NR ₂ , vi) -NR ₂ ,

SHE

II vii) -NHCR.

viii) C 1-4 alkyl, ix) phenyl,

x) -CF "

R xi) -N-SO ₂ R, xii) -OP (O) (OR ₂ or xiii) -COR,

II

b) (C 1 -C 4 alkyl) -NR ₂ , or

SHE

II

c) -OC- (C 1 -C 4 alkyl) substituted with one or more amino or quaternary amino groups or -OP (O) (OR _X ) ₂ ;

3) a heterocyclic group such as isochroman, chroman, isothiochroman, thiochroman, benzimidazole, benzothiopyran, oxobenzothiopyran, benzopyran, benzothiopyranyl sulfone, benzothiopyranyl sulfoxide; wherein the ring or rings are unsubstituted or substituted with one or more of the following groups:

a) R ¹⁴ where R ¹⁴ is as defined above,

b) -O- (C 1 -C 4 alkenyl) -;

c) phenyl (C 1 -C 4 alkyl),

SHE

II

d) -OC- (C 1 -C 4 alkyl) having one or more amino or quaternary amino groups or -OP (O) (OR _X ) ₂ or -O [(CH ₂ ) _m 0] _n -R ;

SHE

II

e) -OCO [(CH ₂ ), "O]" - R, or

4) a 5-7 membered carbocyclic ring or a 7-10 membered bicyclic carbocyclic ring such as cyclopentane, cyclohexane, indane, norbomane, naphthalene, thiopyran, isothiopyran or benzopyran, wherein the carbocyclic ring ring is unsubstituted or substituted with one or more of the following groups:

a) R ¹⁴ , wherein R ¹⁴ has the same meaning as defined above,

b) -CH ₂ OR,

c) - (CH ₂ ) _n -NR ₂ , C 5 -C 16 alkyl, pyridyl,

SHE

II (CH ₂ ) "NR- (CII,)" - NR ₂ , - (CH ₂ ) "- C - () R, .l ((H ₂ )," OJ "-R,» ··

·. · · ·. . ·

......... · quinuclidinium which is substituted with R, piperazine (C 1-4 alkyl) benzyl which is mono- or polysubstituted with R or morpholino (1-4). (C 1 -C 4 alkyl) benzyl,

SHE

d) -OC- (C 1 -C 4 alkyl) substituted with one or more amino or quaternary amino groups, or -OP (O) (OR _X ) _: or -O [(CH ₂ ) _m O] _n - R;

SHE

II

e) -OCO - [(CH.) _m O] "- R, or

f) - (C 1 -C 4) alkyl-phenyl;

Preferred are compounds of formula I wherein

2

R and R are bonded to each other such that together with the nitrogen atom to which R ¹ is attached form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and C 2 to C 9 attached to R ¹ and unsubstituted or substituted with the following groups:

1) a hydroxyl group,

2) C 1 -C 4 alkyl, unsubstituted or substituted with one or more of the following groups:

a) a hydroxy group,

b) C 1-3 alkoxy;

c) an aryl group,

d) 5-7 membered cycloalkyl, unsubstituted or substituted with one or more of the following groups:

i) halogen, ·· * · ii) hydroxy, iii) C 1-3 alkoxy, or iv) aryl,

(e) a heterocyclic group; or

f) -NR ₂ ,

3) C 1-3 alkoxy,

SHE

4) -NH-CO (C 1-3 alkyl),

SHE

II

5) -NH-C- (C 1 -C 3) alkyl,

6) -NH-SO ₂ - (C 1 -C 3) alkyl,

7) -W-aryl, or

8) -W-C-aryl, wherein W is -O-, -S- or -NH-; obsession

SHE

R and R are linked in such a way that together with the nitrogen atom to which R ¹ is attached form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and 1 to 8 carbon atoms attached to R 'and unsubstituted or substituted with the following groups:

1) N,

io

VR ¹ II where V is absent or -CQ- or -SO ₂ -Q- where

1 2

R is as defined above for RR independently of meaning and is not related to R ² , and

Q is absent or represents a heterocyclic group substituted with -O-, -NR-, or optionally substituted with C 1 -C 4 alkyl,

2) -N- (C 1 -C 4 alkenyl) unsubstituted or substituted with aryl],

3) -S (O) _p -, wherein p is 0, 1 or 2, or

4) -O-, or

R and R may be linked to each other such that together with the nitrogen atom to which R ¹ is attached, forms a 3- to 10-membered monocyclic or bicyclic ring system containing a nitrogen atom to R ¹ and 2 to 9 carbon atoms, wherein the saturated the ring system is fused to a phenyl ring and the phenyl ring is unsubstituted or substituted with one or more of the following groups:

1) C 1-3 alkoxy;

2) hydroxy,

3) C 1-4 alkyl,

4) -NHR ¹ , wherein R ¹ is as defined above for R ¹ independently of R ² and is not linked to R.

Even more preferred are the compounds of the invention having the formula

R and R are bonded to each other such that together with the nitrogen atom to which R ¹ is attached form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and C 2 to C 9 attached to R ¹ and unsubstituted or substituted with the following groups:

1) a hydroxyl group,

2) C 1 -C 4 alkyl, unsubstituted or substituted with one or more of the following groups:

the)

b)

c) a hydroxy group,

C 1-3 alkoxy, aryl,

d) 5-7 membered cycloalkyl, unsubstituted or substituted with one or more of the following groups:

(i) halogen, (ii) hydroxy, (iii) C 1-3 alkoxy, or (iv) aryl,

(e) a heterocyclic group; or

f) -NR ₂ ,

3) C 1-3 alkoxy,

SHE

II

4) -NH-CO (C 1-3 alkyl),

SHE

II

5) -NH-C- (C 1 -C 3) alkyl,

6) -NH-SO ₂ - (C 1 -C 3) alkyl,

7) -W-aryl, or

8) -W-C-aryl, wherein W is -O-, -S- or -NH-; obsession

SHE

R ¹ and R ² are bonded to each other such that together with the nitrogen atom to which R ¹ is attached form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and 1 to 8 carbon atoms attached to R 1 and unsubstituted or substituted with the following groups:

1) N,

io

VR ¹ || wherein V is absent or is -CQ- or -SO ₂ -Q-, wherein

R ¹ is as defined above for R ¹ independently of R ² and is not linked to R, and

Q is absent or represents a heterocyclic group substituted with -O-, -NR-, or optionally substituted with C 1 -C 4 alkyl,

2) -S (O) _p -, wherein p is 0, 1 or 2, or

3) -O-,

R ³ represents a benzyl group which is unsubstituted or substituted with one or more of the following groups:

a) a hydroxy group,

b) -NO ₂ or -NR ₂ ,

c) C 1-4 alkyl;

d) C 1-3 alkoxy, unsubstituted or substituted with one or more -OH or C 1-3 alkoxy,

e) -CNR ₂ ,

SHE

f) -CH ₂ NR ₂ ,

SHE

II

g) -ch ₂ nhcr,

h) -cf ₃ , o

II

(i) -NHCR,

j) -NRSO ₂ R,

k) -OP (O) (OR _x ) ₂ or

l) -R ⁵ ;

and B is absent.

Most preferred are the compounds of the invention

X is -OH;

Z is -O;

R and R 'are linked in such a way that the nitrogen atom

- to which R ¹ is attached - together form a 3- to 10-membered monocyclic or bicyclic ring system containing nitrogen and C 2 to C 9 attached to R ¹ and which is unsubstituted with either -W-aryl or -WC-aryl

II is substituted; or O

R and R 'are linked in such a way that the nitrogen atom

- to which R ¹ is attached - together form a 3- to 10-membered monocyclic or bicyclic saturated ring system which is formed of the nitrogen and C 1 -C 8 attached to R * and a -N-,

I o

Consists of VR ¹ groups, || wherein V is absent or is -CQ- or -SO ₂ -Q-, wherein

1 2

R is as defined above for R independently of R and is not linked to R, and

Q is absent or represents a heterocyclic group substituted with -O-, -NR-, or optionally substituted with C 1 -C 4 alkyl,

R is a benzyl group which is unsubstituted or substituted with one or more of the following groups:

1) a hydroxyl group,

2) C 1 -C 3 alkoxy substituted with one or more -OH, or

3) a group of formula (e);

J ¹ is -NH- (C 1 -C 4 alkyl); and

J is a group of formula (f) or (g).

The most preferred compounds of the invention are the following compounds of formulas A-H and J:

.......

Compound A:

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) phenylmethyl-4 (S) -hydroxy-5- {2- [3 (S) -N '- (t -butyl-carbamoyl) - (4aS, 8aS) decahydroisoquinoline] yl} pentanamide;

Compound B:

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4-carbobenzyloxy-2 (S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide;

Compound C:

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl] methyl} -4 (S) - hydroxy-5- {2- [3 (S) -N '- (t-butylcarbamoyl) - (4aS, 8aS) decahydroisoquinoline] yl} pentanamide;

Compound D: N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [[4- [2- (4-morpholinyl) ethoxy] phenyl} methyl] -4 (S) -Hydroxy-5- {1- [4-carbobenzyloxy-2 (S) -N '- (tert-butylcarbamoyl) -piperazinyl]} - pentanamide;

Compound E:

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) ethoxy] phenyl] methyl} -4 (S) -hydroxy- 5- {2- [3 (S) -N '- (tert-Butylcarbamoyl) - (4aS, 8aS) -decahydroisoquinoline] -yl} -pentanamide;

Compound F: N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) -ethoxy] -phenyl} -methyl] -4 (S) ) hydroxy-5- {1- [4-carbobenzyloxy-2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

Compound G:

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {2- [ 3 (S) -N '- (t-butylcarbamoyl) - (4aS, 8aS) decahydroisoquinoline] yl} pentanamide;

Compound H:

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4 -carbobenzyloxy-2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

Compound J: (designated L-735,524)

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4- (3-pyridylmethyl) - 2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide.

The novel compounds of the present invention include, but are not limited to, the following:

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -phenoxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -2-naphthyloxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -l-naphthyloxy-L-prolinamide] yl} pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) phenylmethyl-4 (S) -hydroxy-5- {2- [3 (S) -N '- (t -butyl-carbamoyl) - (4aS, 8aS) decahydroisoquinoline] yl} pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4- (3-phenyl-propionyl) - 2 (S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4-benzoyl-2 (S) -N '- (tert-butylcarboxamido) piperazinyl]} - pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- (4- (3-phenylpropyl) -2 ( S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -amino-5- {1- [4-carbobenzyloxy-2 (S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl} methyl] -4 (S) - hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -phenoxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl]} - methyl] -4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -2-naphthyloxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl] methyl} -4 (S) - hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -1-naphthyloxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -hydroxy-l (S) -indaniI] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl] methyl} -4 (S) - amino-5- {2- [3 (S) -N '- (tert-butylcarbamoyl) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl} methyl] -4 (S) - hydroxy-5- {1- [4- (3-phenylpropionyl) -2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4- [2- (4-morpholmyl) ethoxy] phenyl} methyl] -4 (S) - hydroxy-5- {1- [4-benzoyl-2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl} methyl] -4 (S) - hydroxy-5- {1- [4- (3-phenylpropyl) -2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4- [2- (4-morpholinyl) ethoxy] phenyl} methyl] -4 (S) - amino-5- {1- [4-carbobenzyloxy-2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) -ethoxy] -phenyl} -methyl] -4 (S) -hydroxy-5 - {1- [N '- (tert-butyl) -4 (S) -phenoxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) ethoxy] phenyl} -methyl-4 (S) -hydroxy-5 - {1- [N '- (tert-butyl) -4 (S) -2-naphthyloxy-prolinamide] -yl} -pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) -ethoxy] -phenyl} -methyl] -4 (S) - hydroxy-5- {1- [N '- (tert-butyl) - (S) -1-naphthyloxy-prolinamide] -1] -pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) -ethoxy] -phenyl} -methyl] -4 (S) -amino- 5- {2- [3 (S) -N '- (tert-Butylcarbamoyl) - (4aS, 8aS) -decahydroisoquinoline] -1'-pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) ethoxy] phenyl] methyl} -4 (S) -hydroxy- 5- {1- [4- (3-phenylpropyl) -2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) ethoxy] phenyl] methyl} -4 (S) -hydroxy- 5- {1- [4-Benzoyl-2 (S) -N '- (tert-butylcarbamoyl) -piperazinyl]} - pentanamide;

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) ethoxy] phenyl] methyl} -4 (S) -hydroxy- 5- {1- [4- (3-phenylpropyl) -2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [{4 - [(2-hydroxy) -ethoxy] -phenyl} -methyl] -4 (S) -amino- 5- {1- [4-Carbobenzyloxy-2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide;

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -phenoxy-L-prolinamide] yl} pentanamide;

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -2-naphthyloxy-L-prolinamide] pentanamide yl};

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [N '- (tert-butyl) -4 (S) -l-naphthyloxy-L-prolinamide] yl} pentanamide;

N- [4 (S) -3,4-dihydro-lH-2,2-dioxo-benzo-thiopyranyl] -2 (R) phenylmethyl-4 (S) -amino-5- {2- [3 (S) -N '- (t-butylcarbamoyl) - (4aS, 8aS) decahydroisoquinoline] yl} pentanamide;

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [ 4- (3-phenylpropionyl) -2 (S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide;

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4 benzoyl-2 (S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide;

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1- [4 - (3-phenylpropyl) -2 (S) -N '- (t-butylcarbamoyl) piperazinyl]} - pentanamide; obsession

N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -amino-5- {1- [4 -carbobenzyloxy-2 (S) -N '- (tert-butylcarbamoyl) piperazinyl]} pentanamide.

The compounds of the invention may have asymmetric centers and thus exist in the form of racemates, mixtures of racemates and individual diastereomers or enantiomers, each of which is within the scope of the invention.

In the event that any of the groups represented by multiple moieties (e.g., aryl, heterocyclic, R, R, R, A, η, Z, etc.) occurs more than once in any of the components or in formula (I), then they are reported at each occurrence independently of any other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

Throughout this specification, unless otherwise indicated, "alkyl" means a branched or straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms (Me = methyl, Et = ethyl, Pr = propyl, Bu = butyl); "Alkoxy" means a labeled alkyl group bonded through an oxygen atom; and "cycloalkyl" refers to a saturated cyclic group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cyh) and cycloheptyl. By "alkenyl" is meant a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds which may be present at any stable point in the chain, such as ethenyl, propenyl, butenyl, pentenyl and the like. similar groups. By "alkynyl" is meant a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds which may be present at any stable point on the carbon chain, such as ethynyl, propynyl, butynyl, pentynyl and the like. By "halogen" is meant fluorine, chlorine, bromine and iodine; and "counterion" refers to small single negatively charged particles such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, tartrate, hemitartarate, benzenesulfonate and similar ions.

Unless otherwise indicated, "aryl" means phenyl (Ph) or naphthyl. By "carbocyclic group" is meant a stable 5-7 membered ring containing carbon atoms or a 7-10 membered ring containing bicyclic carbon atoms, which rings may be saturated or unsaturated.

Unless otherwise indicated, a heterocyclic or heterocyclic group includes a stable 5- to 7-membered mono- or bicyclic or a stable 1 to 4-membered bicycle.

refers to a luscious heterocyclic ring system, any of which rings may be saturated or unsaturated and which contains carbon atoms and 1 to 3 heteroatoms such as N, O and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom optionally quaternized, and also bicyclic groups in which any of the heterocyclic rings defined above may be fused to a benzene ring. The heterocyclic ring may be attached via any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxo-piperazinyl, 2-oxo-piperidinyl, 2-oxo-pyrrolidinyl, 2-oxo-azepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidin thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoloyl, benzopyranyl, bemzothiazolyl, benzoxazolyl, furyl, tetrahydrofuran, , benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl. The morpholino group is the same as the morpholinyl group.

Pharmaceutically acceptable salts (in the form of water or oil-soluble or dispersible products) of the compounds of formula (I) may be conventional non-toxic salts or quaternary ammonium salts which may be formed, for example, with inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, lactate -, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate,

Salts of 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. The basic salts may be ammonium salts; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium salts; organic base salts such as dicyclohexylamine salts,,-methyl-D-glucamine, and amino acid salts such as arginine, lysine salts and the like. The basic nitrogen-containing groups can be quaternized with, for example, (lower alkyl) halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; aralkyl halides such as benzyl and phenethyl bromide and the like. Pharmaceutically acceptable salts include the sulfate salt etanulate and the sulfate salt.

The process for preparing the novel compounds of the present invention is illustrated in Schemes 1 to 3. The compounds obtainable by the methods outlined in the Schemes are summarized in Tables 1 and 2. Of course, the compounds and substituents in the Schemes and the compounds described in the Tables are intended to illustrate the invention and are not intended to limit the scope of the invention to these compounds.

The amide coupling agents used to form the compounds of this invention are generally formed with reagents of the carbodiimide process, such as dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Other methods of forming an amide or peptide bond include, but are not limited to, acidic, azide, mixed anhydride, or activated ester synthetic pathways. In general, a solution-phase amide coupling agent is used, but solid-phase syntheses using classical Merrifield techniques may be used instead. In the processes, one or more protecting groups may be formed or removed, as is customary in the art.

As a technical background for the synthesis of the compounds of the invention, reference is made to EPO 0 337 714.

A process for the preparation of compounds of formula I according to the invention is illustrated in Scheme 1. In the scheme, the dihydro-5 (S) - (tert-butyldimethylsilyloxymethyl) -3 (2H) -furanone of formula (1) may be prepared by a standard known procedure using a commercially available dihydro-5 (S) - (hydroxymethyl) -2 (3H) -furanone. Alkylation of the compound of formula (I) can give compounds of formula (2), wherein the lactone of formula (2) is deprotected with aqueous HF to give compounds of formula (3).

The alcohol group of compound (3) is activated by conversion to a leaving group such as mesylate, tosylate or triphthalate by treatment of the alcohol with a sulfonyl chloride or sulfonic anhydride such as trifluoromethanesulfonic anhydride, e.g. in the presence of diethyl isopropylamine or 2,6-lutidine to give an activated compound such as 4. The leaving group of compound (4) is replaced by an amine (5) such as N '- (tert-butyl) - (4aS, 8aS) - (decahydroisoquinoline) -3 (S) -carboxamide in a high melting point solvent, such as DMF or xylene to prepare compounds of formula (6). Trifluoromethanesulfonyloxy groups may be substituted by amine groups at room temperature by treatment with Ν, iz-diisopropylethylamine in a solvent such as isopropanol.

The compounds of formula (6) are hydrolyzed with aqueous lithium or sodium hydroxide and the resulting hydroxy acids (7) are converted to the protected hydroxy acids (8). The hydroxyl group may be protected by a standard silyl protecting group such as a tert-butyldimethylsilyl or a tert-butyldiphenylsilyl protecting group by a conventional protecting group.

The protected hydroxy acid (8) is then coupled with the desired R-amine to form the compound (9) and the silyl

deprotecting with a fluoride ion to form compounds of formula (10).

A second process for the preparation of compounds of formula (I) according to the invention is illustrated in Scheme 2. In the procedure outlined in Scheme 2, the compound of formula (11) is first alkylated and deprotonated with n-butyllithium or lithium diisopropylamide (LDA), and in the second step, an alkenyl halide (such as allyl) is added to the resulting compound. bromide), for example, to give compound 12.

Dehydroxylation of the olefin (12) with osmium tetroxide and N-methylmorpholine-N-oxide (NMO) yields a diastereomeric mixture of diols (13). Selective mesylation of the primary alcohol 13 by treatment with methanesulfonyl chloride and triethylamine or pyridine gives the mesylate 14.

The mesylate 14 is heated with an amine in an alcohol such as methanol or isopropanol containing excess potassium carbonate and the solvent is refluxed to give the amino alcohol 15. In this step, the diastereoisomers may be separated using standard techniques well known in the art. Alternatively, separation may be effected after removal of the ketal.

The removal of the ketal group in the compound of formula (15) may be accomplished by acidic treatment in the presence of an alcohol or by aqueous acid treatment or by treatment with IN hydrochloric acid in THF. In this way, compounds of formula 16 are obtained.

A third process for the preparation of compounds of formula I is illustrated in Scheme 3. The -NH group of pyrrolidine (17) is protected with BOC anhydride and dimethylaminopyridine. This way

.......

yielding the protected compound of formula (18). Compound (18) is alkylated by deprotonating compound (18) with a strong base such as lithium hexamethyldisilamide (LHMDS) or lithium diisopropylamide (LDA) in the first step, and then in the second step. an alkyl halide (such as benzyl bromide) is added. In this way, the compound of formula (19) is obtained.

The TBS and BOC protecting groups of the compound of formula (19) are removed by treatment with aqueous hydrogen fluoride in acetonitrile. The alcohol (20) is thus obtained. The primary alcohol (20) is mesylated with methanesulfonyl chloride and triethylamine or pyridine. Mesylation gives mesylate 21 which is heated to reflux with an amine in an alcoholic solvent such as methanol or isopropanol which contains excess potassium carbonate to give aminopyrrolidinone 22. The -NH group of pyrrolidine (22) is protected with BOC as described above and the resulting compound (23) is hydrolyzed with a base such as lithium or sodium hydroxide. This gives the acid (24), which is coupled in a standard manner with an amine (NH ₂ R), and then the BOC protecting group is removed with gaseous HCl or trifluoroacetic acid to give the desired compound, such as 25.

Compounds of formula (26) wherein P is a nitrogen protecting group, such as -BOC or -CBZ, are preferably prepared according to the procedure outlined in Scheme 1 and described above, preferably 5-trifluoromethanesulfonyloxymethyl analog (4). ) using lactone (see Example 15, Step 1).

Compounds of formula (27) can be prepared from compounds of formula (28) via a number of pathways, the latter being obtained by removing the nitrogen protecting group of compound (26) by methods well known in the art, such as CBZ by catalytic hydrogenation of the protecting group or by treatment with trimethylsilyl triflate and 2,6-lutidine in a solvent such as CH ₂ Cl ₂ at 0 ° C.

For example, the compound of formula (28) is in the piperazinyl group

4-nitrogen atom alkylated with a ^RJ-X compound, wherein at room temperature, or a sulfonamide group can be converted to X = -Cl, -Br or -I, DMF, Et ₃ N in the presence of the formula in such a manner that the formula (28) compound with a sulfonyl chloride of formula r'SO C1 ₂ under similar reaction conditions. Standard amide coupling techniques may also be used to form the amide group at the 4-position of the piperazinyl ring. These production methods are well known in the art. In the compounds of formula R'-X or r's O ₂ Cl, the group R ¹ is as defined above for compound of formula (I) wherein R is independent of R and R is not attached to R, except that R is not a hydrogen atom or a group substituted with a free hydroxyl substituent, such as a C 1-4 alkyl group substituted with a hydroxy group, except that R ¹ can also be an aryl group substituted with a hydroxy group.

1-4. Tables are presented.

• v ·· »V • · · · · ♦ ·· ♦ ··

Table 1

R ³

-CH ₂ -Ph

-CH ₂ -Ph

-CH ₂ -Ph

-CH ₂ -Ph

Table 1 (continued) • V • · ··

R ³

-CH ₂ -Ph

OH

-CH ₂ -Ph

OH

-CH ₂ -Ph

-CH ₂ -Ph

OH

OH

-CH ₂ -Ph

OH

-CH ₂ -Ph

OH

• *

Table 1 (continued)

SHE

-CH ₂ -Ph -OH

Ο N H

Table 1- (continued)

R ³

-CH ₂ -Ph

OH

NH

-CH ₂ -Ph

-NH ₂

NH

-CH ₂ -Ph

OH

-CH ₂ -Ph

OH

-CH ₂ -Ph

NH ₂

-CH ₂ -Ph

OH

NH k ..OH

Table 1 (continued)

Table 1 (continued)

Template (continued)

Table 1 (continued)

SHE

-CH ₂ CH = CH-Ph

OH

-CH ₂ CH = CH-Ph

S == O

SHE

Table 1 (continued)

z ^ yCONH- | -

C.com | N / x.CONH-1LzN2. spreadsheet

X

OH

OH

-NH ₂

-nh ₂

OH

Table 2 (continued)

CONH - | CONH CONH ~

CONH-OH

OH

OH

-NH ₂

OH

OH

Table 2 (continued)

OH

OH

• · · »· ·» · * · · *

Table 2 (continued)

OH

OH

OH

Table j- (continued)

OH

OH

Table 2 (continued)

OH

OH

'CONH OH

OH

Table 2 (continued) • · »» »• · · ··· * • ·« * <»« · 4t · «· * · ·»

♦ · ♦ ·· - «· ·« «« ♦ ♦ ♦ ♦ ♦ ♦ * *

Table 3

Ph

Table 4

(CH ₃ ) ₃ CO <U

Ph-CH ₂ CH ₂ 51

The compounds of the invention are useful in the preparation and overview of antiviral compounds. For example, the compounds of the present invention are useful as enzyme mutants, which are excellent assays for screening for more potent antiviral compounds. Further, the compounds of the present invention may be used to generate or determine the binding site of other antiviral agents to HIV protease, for example by competitive inhibition. Thus, the compounds of the invention are commercially available for these purposes.

The compounds of the invention are useful in the inhibition of HIV protease, in the prevention or treatment of infection by human immunodeficiency virus (HIV), and in the treatment of pathological conditions such as AIDS. The treatment of AIDS or the prevention or treatment of HIV infection includes, but is not limited to, a broad range of conditions of HIV infection: AIDS, ARC (AIDS-related complex), both symptomatic and asymptomatic, and those that are or may be exposed to HIV infection. For example, the compounds of the present invention may be used in the treatment of HIV infection after being likely to be infected with HIV, such as blood transfusion, organ transplantation, body fluid exchange, accidental injection needle infection, or surgical blood supply.

For these purposes, the compounds of the invention may be administered orally, parenterally (including subcutaneous injection, intravenous, intramuscular, intrastemal injection or infusion modes of administration), by inhalation spray, or rectally in unit dosage forms containing conventional non-toxic pharmaceutically acceptable excipients, They contain.

The present invention also relates to a method of treatment and a pharmaceutical composition for treating HIV infection and AIDS. The method of the invention comprises administering to a patient in need of such treatment a pharmaceutical composition of the invention comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

These pharmaceutical compositions may be in the form of oral suspensions or tablets, nasal sprays, sterile injectable preparations such as sterile injectable aqueous or oleaginous suspensions or suppositories.

Suspension preparations for oral administration may be formulated according to techniques well known in the art. These compositions may contain microcrystalline cellulose as a carrier, alginic acid or sodium alginate as a suspending agent, and methylcellulose as a viscosity enhancer, and may also contain sweetening / flavoring agents known in the art. The immediate release tablet formulations may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other carriers, excipients, fillers, disintegrating agents, lubricants and lubricants known in the art.

Nasal aerosol or inhalation formulations may also be prepared by methods well known in the art. These formulations may be formulated as solutions in saline using benzyl alcohol or other suitable preservatives, and absorption enhancers, fluorocarbons and / or other solubilizing or dispersing agents known in the art may be used to enhance bioavailability.

Injectable solutions or suspensions may be formulated according to the art in suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable disintegrating or wetting agents and suspending agents, such as sterile, non-infectious, hardened oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

Suppositories for rectal administration may be formulated so that the drug is formulated with a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols which are solid at normal temperature but become liquid or rectal. dissolve and thus release the drug, mix.

The daily dosage for treating or preventing the above conditions is 0.02-5.0 g or 10.0 g, which is 2-5 times the oral dose. For example, effective treatment for HIV infection requires a daily dose of 1-4 x 1.0-50 mg / kg body weight. Preferably, 100-400 mg of compound is administered orally every 6 hours. However, it will be appreciated that the particular dose level and frequency of administration will vary from patient to patient and will depend on various factors such as the activity, metabolic stability and lifetime of the compound, and the age, weight, general condition, sex, diet of the patient. , the mode and time of dosing, the frequency of emptying, other drugs administered, the severity of the condition, and the host to be treated.

The invention also relates to combinations of HIV-protease inhibitor compounds and one or more agents effective in treating AIDS. For example, the compounds of the present invention may be administered in a pre-infection rich and / or post-infection period in combination with an effective amount of prior art AIDS antiviral agents, immunomodulators, anti-infectives or vaccines. These known agents are summarized in Table C below.

C.táblázat

Antivirals

pharmaceutical Name Manufacturer indications AL-721 Ethigen (Los Angeles, CA) ARC, PGL, HIV positive, AIDS Recombinant Human Interferon Beta Triton Biosciences (Almeda, CA) AIDS, Kaposi's sarcoma, ARC acemannan Carrington Labs (Irving, TX) ARC (see also immunomodulators) Cyctovene Ganciclovir Syntex (Palo Alto, CA) CMV, peripheral CMV, peripheral ocular inflammation d4T didehydro-deoxythymidine Bristol-Myers (New York, NY) AIDS, ARC ddl didezoxinosine Bristol-Myers (New York, NY) AIDS, ARC EL10 Elán Corp., PLC (Gainesville, GA) HIV infection (see also immunomodulators) Disodium Phosphonoformate Astra Pharm. Products., Inc. (Westborough, MA) CMV eye inflammation, HIV infection, other CMV infections Dideoxycytidine, ddC Hoffinan-La Roche (Nutley, NJ) AIDS, ARC Novapren Novaferon Labs, Inc. (Akron, OH) Diapren Inc. (Roseville, MN, distributor) HIV inhibitor Peptide T, Octapeptide, Sequence Peninsula Labs (Belmont, CA) AIDS Zidovudine, AZT AIDS, adv., ARC Burroughs Wellcome (Rsch. Triangle Park, NC) AIDS, adv, ARC, childhood AIDS, Kaposi's sarcoma, asymptomatic HIV infection, less severe HIV disease, neurological damage in combination with other therapies

pharmaceutical Name Manufacturer indications Ansamycin LM 427 Adria Laboratories (Dublin, OH) Erbamont (Stamford, CT) FACE Dextran Sulfate Ueno Fine Chem. Ind. Ltd. (Osaka, Japan) AIDS, ARC, Positive Asymptomatic Call Virazole, Ribavirin Viratek / ICN (Costa Mesa, CA) positive asymptomatic CALL Alpha Interferon Burroughs Wellcome (Rsch. Triangle Park, NC) Kaposi's sarcoma in combination with Retrovir in HIV acyclovir Burroughs Wellcome AIDS, ARC, asymptomatic HIV positive, in combination with AZT Antibody that neutralizes pH-sensitive alpha aberrating Interferon on an immuno-adsorption column Advanced Biotherapy Concepts (Rockville, MD) AIDS, ARC L-697,661 Merek (Rahway, NJ) CALL Positive AIDS, ARC, asymptomatic call, also in combination with AZT L-696.229 Merek (Rahway, NJ) is asymptomatic AIDS, ARC, asymptomatic call, also in combination with AZT AS-101 Wyeth-Ayerst Labs. (Philadelphia, PA) (Kalamazoo, MI) AIDS, advanced AIDS bropirimine Upjohn (Kalamazoo, MI) advanced AIDS acemannan Carrington Labs, Inc. (Irving, TX) AIDS, ARC (see also antivirals) CL246,738 American Cyanamid (Pearl River, NY) Lederle Labs (Wayne, NJ) AIDS, Kaposi's sarcoma EL10 Elán Corp., PLC (Gainesville, GA) HIV infection (see also antivirals) Gamma Interferon Genentech (S. San Francisco, CA) ARC in combination with TNF (tumor necrosis factor) granulocyte Macrophage Colony Stimulating Factor Genetics Institute (Cambridge, MA) Sandoz (East Hanover, NJ) AIDS Granulocyte Macrophage Colony Stimulating Factor Hoechst-Roussel (Sommerville, NJ) Immunex (Seattle, WA) AIDS

pharmaceutical Name Manufacturer indications granulocyte Macrophage Colony Schering-Plow (Madison, NJ) AIDS Stimulating Factor AIDS, in combination with AZT NEWS Core Party Immunostimulant Rorer (Ft. Washington, PA) seropositive NEWS IL-2 Interleukin-2 Cetus (Emeryville, CA) AIDS, in combination with AZT IL-2 Interleukin-2 Hoffman-La Roche (Nutley, NJ) Immunex AIDS, face, call, AZT Immune Globulin Intravenous (Human) Cutter Biological (Berkeley, CA) childhood AIDS in combination with AZT IMREG-1 Imreg (New Orleans, LA) AIDS, Kaposi's sarcoma, ARC, PGL IMREG-2 Imreg (New Orleans, LA) AIDS, Kaposi's sarcoma, ARC, PGL Imutiol diethyl dithiocarbamate Merieux Institute (Miami, FL) AIDS, ARC Alpha-2 Interferon Schering-Plow (Madison, NJ) Kaposi's sarcoma with AZT, AIDS Methionine enkephalin TNI Pharmaceutical (Chicago, IL) AIDS, ARC MTP-PE muramil tripeptides Ciba-Geigy Corp. (Summit, NJ) Kaposi's sarcoma Granulocyte Colony Stimulaging Factor Amgen (Thousand Oaks, CA) AIDS, in combination with AZT rCD4 Recombinant Soluble Human CD4 Genentech (S. San Francisco, CA) AIDS, ARC rCD4-IgG hybrids AIDS, ARC Recombinant Soluble Human CD4 Biogen (Cambridge, MA) AIDS, ARC Interferon Alpha 2a Hoffman-La Roche (Nutley, NJ) Kaposi's sarcoma, AIDS, ARC, in combination with AZT SK & F106528 Soluble T4 Smith, Kline & French Laboratories (Philadelphia, PA) HIV infection thymopentin Immunobiology Research Institute (Annandale, NJ) HIV infection Tumor Necrosis Factor, TNF Genentech (S. San Francisco, CA) ARC, gamma in combination with Interferon

Anti-infectives

pharmaceutical Name Manufacturer indications Clindamycin Primaquine Upjohn (Kalamazoo, MI) PCP fluconazole Pfizer (New York, NY) cryptococcal rhinitis, candidiasis Pastille Nystatin for Pastille Squibb Corp. (Princeton, NJ) prevention of oral candidiasis Omidyl Erlomithine Merrell Dow (Cincinnati, OH) PCP Pentamidine Isethionate (IM & IV) LyphoMed (Rosemont, IL) PCP management trimethoprim antibacterial Trimethoprim / sulfa antibacterial piritrexim Burroughs Wellcome (Rsch. Triangle Park, NC) PCP management Pentamidine isethionate for inhalation Fisons Corporation (Bedford, MA) PCP prevention spiramycin Rhohe-Poulenc Pharmaceuticals (Princeton, NJ) cryptosporidial diarrhea Itraconazole-R51211 Janssen Pharm. (Piscataway, NJ) histoplasmosis, cryptococcal reningitis trimetrexate Wamer-Lambert PCP

Other

pharmaceutical Name Manufacturer indications Recombinant human Erythropoietin Ortho Pharm. Corp. (Raritan, NJ) severe anemia with AZT therapy Megestrol Acetate Bristol-Myers (New York, NY) Treatment of AIDS-related anorexia Total Enteral Nutrition Norwich Eaton Pharmaceuticals (Norwich, NY) AIDS-related diarrhea and malabsorption

It will be appreciated that combinations of the compounds of the invention with other AIDS antiviral agents, immunomodulators, anti-infectives or vaccines are not limited to the substances listed in the table above, but include in principle any combination of pharmaceutical preparations for treating AIDS.

The compounds indicated in Table C are: L-697,661 or '661' = 3 - {[(4,7-dichloro-1,3-benzoxazol-2-yl) methyl] amino} -5-ethyl -6-methylpyridin-2 (lH) -one; L-696,229 = 3- [2- (1,3-Benzoxazol-2-yl) ethyl] -5-ethyl-6-methylpyridin-2 (1H) -one. The synthesis of L-697,661 and L-696,229 is described in EPO 484 071 and EPO 462 800. The synthesis of ddC, dd1 and AZT is described in EPO 484 071.

Preferred combinations are those that simultaneously or alternately treat an HIV-protease inhibitor and a HIV-reverse transcriptase non-nucleoside inhibitor. A third component optionally present in the combination is a HIV reverse transcriptase nucleoside inhibitor such as AZT, ddC or dd1. A preferred inhibitor of the HIV protease is L-735,524 (Compound J). HIV reverse non-nucleoside inhibitors include L-697,661. These combinations may have a synergistic effect in limiting the spread of HIV. Further preferred combinations are: (1) L-735,524 with L-697,661 and optionally AZT or ddl or ddC; (2) L-735,524 and any one of AZT, ddl or ddC.

Inhibition of microhistically expressed HIV protease

Inhibition of the protease reaction in 50 mM sodium acetate at pH 5.5 at 30 ° C for 1 hour on a peptide substrate [Val-Ser-Gln-Asn- (beta-naphthyl) -Ala-Pro-Ile-Val, 0.5 mg / ml at the initiation of the reaction) was tested in the expressed Eschericia co. To 25 μΐ aqueous peptide solution was added 1.0 μΐ DMSO containing various concentrations of inhibitor. The reaction was initiated by addition of a solution containing 0.133 M sodium acetate (pH 5.5) and 15 μΐ, 0.33 nmol / L protease (0.11 ng), and 0.1 wt% horn bovine serum albumin. The reaction was quenched with 160 μΐ of 5% phosphoric acid. Reaction products were obtained by high pressure liquid chromatography (VYDAC broad pore, 5 cm, C-18 reverse phase, acetonitrile gradient, 0.1 wt% phosphoric acid). The degree of inhibition of the reaction is determined from the peak heights of the products. High performance liquid chromatography (HPLC) of independently synthesized products provided quantitative standards and strengthened product composition. 1-7. The products synthesized in Examples 1 to 4 have an IC _{50 in the} range of 1-100 nmol / L. Compounds A, B, and J have an IC _{50 in the range of} about 0.3 nM to about 6 nM.

Inhibition of virus spread

A. Preparation of HIV-infected MT-4 cell suspension

On day 0, MT cells at 250,000 / ml were infected with 1: 1000 dilutions of HlV-1 strain, Illb variety (final 125 pg p24 / ml; <1% infected cells on day 1 and 25-100% on day 4). to form an infected cell). The cells were infected and cultured in RPMI 1640 (Whittaker BioProducts), 10% inactivated bovine serum, 4 mM glutamine (Gibco Labs) and 1: 100 penicillin / streptomycin (Gibco Labs).

The mixture was incubated overnight at 37 ° C in 5% CO ₂ .

B. Treatment with Inhibitors

A matrix of nanomolar concentration ranges for each pair combination (see Table S) is prepared. On the first day, an aliquot of 125 μΙ inhibitor was added to an equal volume of HIV-infected MT-4 cells (50,000 / well) in a 96-well microtiter cell culture plate. Incubation was continued for 3 days at 37 ° C and 5% CO ₂ .

C. Measure the spread of the virus

The pelleted cells were resuspended using a five-tip pipette, and 125 μΙ of the suspension was collected on another microtiter plate. The supernatant was assayed for HIV p24 natigen.

The concentration of HIV p24 antigen is measured by an enzyme immunoassay, as described below. Aliquots of the p24 antigen to be measured are added to a microplate holder coated with monoclonal antibody specific for HVV core antigen. Wash the microwellings at this point and the next appropriate steps. Bio-affinity HIV specific antibodies are then added followed by streptavidin horseradish peroxidase. Addition of hydrogen peroxide and tetramethylbenzidine substrate results in a color reaction. The color intensity is proportional to the concentration of HIV p24 antigen.

Calculating the degree of synergism

Paired combinations of inhibitors (see Table S) have been found to inhibit viral spreading to a greater degree than the individual inhibitors alone or by adding only an additive inhibitor to each inhibitor. Thus, for example, the combination of 524 and AZT showed significantly greater inhibition of viral proliferation compared to the data obtained with 524 or AZT alone or the sum of the 524 inhibition and the AZT inhibition.

These data were obtained as follows: Fractional Inhibitor Concentration Ratios (FIC) Elion et al., J. Bioi. Chem., 208, 477 (1954). The minimum sum of FIC values, which corresponds to maximum synergism, was determined for the different paired combinations. The results are summarized in Table S. These results indicate significant synergies in the inhibition of virus spread. Smaller numbers mean greater synergy.

Table S.

Pair Combinations * Maximum synergism 524+ ddl 0.7 524 + AZT 0.7 524 + 661

524 = L-735,524 (Compound J). Other compounds are described in Table C above.

Example 1 N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- [1-ΓΝ '- (tert-butyl) Preparation of -4 (S) -phenoxy-prolinamide] -yl) -pentanamide

Step 1: Preparation of N-12 (R) -hydroxy-1 (S) -indanyl-3-phenylpropanamide in ml dichloromethane, 750 mg (5.0 mmol) 2 (R) -hydroxy-1 (S) A solution of 843 mg (5.0 mmol) of hydrocinnamoyl chloride and 5 ml of dichloromethane was added to a cold solution at 0 ° C containing 606 mg (6.0 mmol) of triethylamine. After 2 hours, the reaction mixture was poured into a separator containing 50 mL of dichloromethane and washed with 2 x 30 mL of 10% citric acid. The organic layer was dried, filtered and evaporated. A white solid is obtained.

Step 2: Preparation of N-r 2 (R) -hydroxy-1 (S) -indan-N, O -isopropylidene-yl-3-phenylpropanamide

The white solid product obtained in Step 1 was dissolved in dichloromethane (50 mL) and p-toluenesulfonic acid (100 mg) was added followed by dimethoxypropane (5 mL). After stirring at room temperature for 18 hours, the reaction mixture was poured into a separatory funnel and washed with saturated sodium bicarbonate (2 x 30 mL). The organic layer was dried, filtered and evaporated. Obtained as an oily substance which is chromatographed (SiO ₂ , 40% by volume EtOAc / hexane). An oily substance is obtained which crystallizes.

Step 3: N-R 2 (R) -Hydroxy-1 (S) -indan-N, O -isopropylidene-yl] -2 (S) -phenyl-

Preparation of methyl-pent-4-enamide

A solution of 1.03 g (2.9 mmol) of N- [2 (R) -hydroxy-1 (S) -indane-N, O-isopropylidene-yl] -3-phenylpropanamide and 20 ml of CHF was cooled. At -78 ° C, n-BuLi (1.40 mL, 2.5 mol, 3.5 mmol) was added. After 20 minutes, 0.48 g (3.9 mmol) of allyl bromide was added to the reaction mixture and the resulting mixture was stirred at -78 ° C for 1 hour. Saturated ammonium chloride solution (10 mL) was then added to quench the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (50 mL), dried, filtered and evaporated. The crude product obtained is purified on silica gel to give the title compound.

Step 4: Preparation of N-r 2 (R) -hydroxy-1 (S) -indan-N, O -isopropylidene-yl-1-2 (S) -phenylmethyl-4 (RS), 5-dihydroxy-1-pentanamide

800 mg (2.2 mmol) of N- [2 (R) -hydroxy-1 (S) -indan-N, O-isopropylidene-yl] -2 (S) -phenylmethyl-pent-4-enamide dissolved in 40 ml of acetone / water (9: 1), then 0.8 ml of a 60% w / v aqueous solution of N-methylmorpholine-N-oxide was added, followed by 4 ml of 25% w / w osmium tetroxide in tert-BuOH. After 18 hours, excess sodium bisulfate solid was added to the reaction mixture, and the reaction mixture was stirred for 2 hours and then filtered through celite. The filtrate was evaporated, diluted with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The organic phase was dried, filtered and evaporated. The title compound is obtained as a foam.

Step 5: N- [2 (R) -Hydroxy-1 (S) -indane-N, O -isopropylidene-yl] -2 (S) -phenylmethyl-4 (RS) -5-methanesulfonyl- Preparation of oxy] pentanamide

200 mg (0.527 mmol) of N- [2 (R) -hydroxy-1 (S) -indane-N, O -isopropylidene-yl] -2 (S) -phenylmethyl- [4 (RS), 5-dihydroxy] Pentanamide was dissolved in dichloromethane (7 mL) at 0 ° C and triethylamine (59 mg, 0.58 mmol) was added followed by methanesulfonyl chloride (66 mg, 0.579 mmol). After 4 hours, the reaction mixture was worked up by washing with 10% citric acid (2 x 50 mL) and the organic phase was dried, filtered and evaporated. The monomesylate is obtained as a mixture of alcohols.

Step 6: Preparation of N '- (tert-butyl) -N-Boc-4 (R) -hydroxy-L-prolinamide in 2 ml of N-Boc-4 (R) -hydroxyproline dissolved in DMF After cooling the solution to 0 ° C, 1.987 g EDC, 1.401 g HOBT, 1.09 ml tert-butylamine and 2.41 ml triethylamine were added. After 18 hours, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate, water, and brine. The solution was dried over magnesium sulfate and evaporated. A white solid is obtained.

Step 7: Preparation of N '- (tert-butyl) -N-Boc-4 (S) -phenoxy-L-prolinamide

To a solution of 0.6 g of N-tert-butyl-N-Boc-4 (R) -hydroxy-L-prolinamide and 5 ml of THF was added 0.295 g of phenol, 0.824 g of triphenylphosphine, followed by 9 0.495 ml of diethyl azodicarboxylate are added dropwise. The reaction mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate (200 mL). The organic solution was then washed with saturated aqueous sodium bicarbonate, water, brine and then dried over magnesium sulfate. The solution was concentrated in vacuo. Obtained as a yellow oil which was purified by flash chromatography (eluent: hexane / EtOAc (1: 1), 30 mm column).

Step 8: Preparation of N- (tert-butyl) -4 (S) -phenoxy-L-prolinamide trifluoroacetic acid salt

To a solution of 0.596 g of N '- (tert-butyl) -N-Boc-4 (S) -phenoxy-L-prolinamide and 4 ml of dichloromethane is added 2 ml of trifluoroacetic acid at 0 ° C. After 30 minutes, the reaction mixture was warmed to room temperature and stirred at this temperature for 10 hours. The solvent was removed in vacuo. Light yellow oil is obtained.

Step 9: N- [2 (R) -Hydroxy-1 (S) -indan-N, O -isopropylidene-yl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5 Preparation of {1-N'-tert-butylPUSj-phenoxy-prolinamidl-yl} -pentanamide

0.36 g of N- (tert-butyl) -4 (S) -phenoxy-L-prolinamide trifluoroacetic acid salt, 0.226 g of N- [2 (R) -hydroxy-1 (S) -indan-N, O]. To a solution of isopropylidene-yl] -2 (S) -phenylmethyl- [4 (RS) -hydroxy-5-methanesulfonyl-pentanamide and 3 ml of isopropanol] was added 0.441 g of potassium carbonate and the resulting reaction mixture was heated to 80 ° C. After 18 hours, the reaction mixture was cooled to room temperature, filtered through celite, and washed several times with EtOAc. The filtrate was evaporated and the residue was dissolved in 100 mL of EtOAc. The solution was washed with water and brine and then dried over magnesium sulfate. The solvent was removed in vacuo. The resulting oily material was purified by flash chromatography. The product is obtained as a mixture of diastereoisomers.

* »» V

Step 10: N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- | Preparation of 1-rN '- (tert-butyl) -4 (S) -phenoxy-prolinainide] -yl) -pentanamide

0.13 g of N- [2 (R) -hydroxy-1 (S) -indane-N, O -isopropylidene-yl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1 To a solution of [N '- (tert-butyl) -4 (S) -phenoxy-prolinamide] -yl} -pentanamide and 5 ml of methanol is added 0.070 g of camphorsulfonic acid (CSA) at room temperature. After 5 hours, additional CSA (0.025 g) was added and the reaction stirred for a total of 18 hours. The reaction was quenched by the addition of 5 ml of saturated sodium bicarbonate solution and the volume was reduced to 4 ml by removal of the solvent. The aqueous layer was extracted thoroughly with EtOAc, and the organic layer was washed with water and brine and then dried. The solvent was removed in vacuo and the resulting oily material was purified by flash chromatography. The title compound is obtained in the form of a white foam. The foam was dissolved in EtOAc / hexane and the mother liquor was decanted from the oil. The oily material was dehydrated in a dessicator under high vacuum. A white foamy material is obtained.

Example 2

N-r 2 (R) -hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {- (tert-butyl) -4 (S) -2- Preparation of naphthyloxy-prolinamide-1-yl) -pentanamide Step 1: Preparation of N-tert-butyl-4 (S) -2-naphthyloxy-L-prolinamide trifluoroacetic acid salt

Example 1-8. Steps 1 through 2 are the same as the procedure for the preparation of the N-tert-butyl-4 (S) -phenoxy-L-prolinamide trifluoroacetic acid salt, but using 2-naphthol instead of phenol to produce 2-naphthyloxy-prolinamide.

• · · · · · «· ··· ·« · · V · »·

Step 2: N-r 2 (R) -Hydroxy-1 (S) -indanyl-2 (R) -phenylmethyl-4 (S) -hydroxy-5-r 1- (N'-tert-butyl-4) Preparation of (S) -2-naphthyloxy-prolinamide) -yl-1-pentanamide

The title compound was prepared according to the procedure described in Example 1, Steps 9 and 10, but replacing the N-tert-butyl-4 (S) -phenoxy-L-prolinamide trifluoroacetic acid salt used in Step 9 with butyl-4 (S) -2-naphthyloxy-L-prolinamide trifluoroacetic acid salt is used.

Example 3 N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {1 - [(tert-butyl)] Preparation of -4 (S) -1-naphthyloxy-prolinamide] -yl} -pentanamide

Step 1: Preparation of N- (tert-butyl) -4 (S) -1-naphthyloxy-L-prolinamide trifluoroacetic acid salt

Example 1-8. In the same manner as in the same steps for the preparation of the N-tert-butyl-4 (S) -phenoxy-L-prolinamide trifluoroacetic acid salt, steps 1-naphthyloxy-prolinamide are prepared using 1-naphthol instead of phenol.

Step 2: N-r 2 (R) -Hydroxy-1 (S) -indanyl-2 (R) -phenylmethyl-4 (S) -hydroxy-5-r 1

- Preparation of (N'-tert-butyl-4 (S) -2-naphthyloxy-prolinamide) -yl-pentanamide

The title compound was prepared according to the procedure described in Example 1, Steps 9 and 10, but replacing the N-tert-butyl-4 (S) -phenoxy-L-prolinamide trifluoroacetic acid salt used in Step 9 with butyl-4 (S) -1-naphthyloxy-L-prolinamide trifluoroacetic acid salt is used.

Example 4 N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5-f 2- [3 (S) ~ -N Preparation of '- (tert-butylcarboxamido) - (4aS, 8aS) -decahydioisoquinolin] -yl 1-pentanamide

V ·· '• · · V · · · · · ν · β> ν · <# ·

Step 1: Preparation of Dihydro-5 (S) - [(tert-butyldiphenylsilyl) oxymethyl] -3 (R) -phenylmethyl-3 (2H) -furanone

To a solution of 0.55 ml (3.9 mmol) of diisopropylamine and 10 ml of THF at -78 ° C is added 1.55 ml of n-BuLi (2.5 molar solution in hexane) to give lithium diisopropyl -amide (LDA). After 30 min, the reaction mixture was treated with 1.38 g (3.89 mmol) of dihydro-5 (S) - [(tert-butyldiphenylsilyl) oxymethyl] -3 (2H) -furanone and 5 mL of THF. is added. After stirring for a further 30 minutes, benzyl bromide (0.68 g, 3.9 mmol) was added. After stirring for a further 3 hours, the reaction was quenched by the addition of 10% aqueous citric acid. The solution was extracted with ethyl acetate (2 x 50 mL) and washed back with brine. The carbon layer was dried, filtered and evaporated. An oily substance is obtained. The product was purified by chromatography (SiO ₂ , 20% EtOAc in hexane). The title compound is obtained.

Step 2: Preparation of Dihydro-5 (S) - (hydroxymethyl) -3 (R) -phenylmethyl-3 (2H) -furanone

To a reaction mixture containing 5.26 g of dihydro-5 (S) - [(tert-butyldiphenylsilyl) oxymethyl] -3 (R) -phenylmethyl-3 (2H) -furanone and 40 ml of acetonitrile, HF (49 mL, 49% w / w) was added. The reaction mixture was stirred at room temperature for 18 hours and then concentrated to dryness. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried and evaporated. The product was obtained as a light brown solid. Melting point: 69-72 ° C.

Step 3: Dihydro-5 (S) - (methanesulfonyloxymethyl) -3- (R) -phenylmethyl-3 (2H) -

production of furanone

A solution of dihydro-5 (S) -hydroxymethyl-3 (R) -phenylmethyl-3 (2H) -furanone (2.93 g, 14 mmol) in dichloromethane was cooled to 0 ° C and Triethylamine (1.98 mL, 15.6 mmol) was added followed by methanesulfonyl chloride (1.20 mL, 15.6 mmol). After 1 hour at 0 ° C, the reaction mixture was poured into 10% aqueous citric acid. The solution was washed with ethyl acetate (2 x 100 mL) followed by water (100 mL) and brine (100 mL). The organic phase was dried, filtered and evaporated. A brown, waxy solid is obtained.

Step 4: Dihydro-5 (S) - {2- [3- (S) -N- (tert-butylcarboxamido) - (4aS, 8aS) - (decahydroisoquinolinyl) -yl] -3- (R ) -phenylmethyl-3 (2H) -furanone mg mg of dihydro-5 (S) - [(methanesulfonyl) oxymethyl] -3 (R) -phenylmethyl-3 (2H) -furanone. N-tert-butyl (4aS, 8aS) - (decahydroisoquinoline) -3 (S) -carboxamide (65 mg, 0.27 mmol) was added to a mixture of xylene (100 ml) and potassium carbonate (100 mg) and the reaction mixture was heated to 140 ° C. 6 hours. The reaction mixture was cooled, poured into water (30 mL) and washed with ethyl acetate (2 x 30 mL). The organic phase was dried, filtered and evaporated. The residue was chromatographed with EtOAc / hexane (50:50) to give the title compound.

Step 5: 2 (R) -phenylmethyl-4 (S) - (tert-butyldimethylsilyloxy) -5-f 2 -f 3 (S) -N-

Preparation of - (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl] -pentanoic acid

130 mg (0.305 mmol) of dihydro-5 (S) - {2- [3 (S) -N- (tert-butylcarboxamido) - (4aS, 8aS) - (decahydroisoquinolin) -yl] methyl} -3 ( To the reaction mixture containing R) -phenylmethyl-3 (2H) -furanone and 2 ml of DMF was added 1 ml of lithium hydroxide solution. After 4 hours at room temperature, the reaction mixture was evaporated to dryness and azeotroped three times with toluene to remove excess water. The residue was dissolved in DMF (5 mL) and imidazole (414 mg, 6.10 mmol) and tert-butyldimethylsilyl chloride (465 mg, 3.05 mmol) were added. After 2 days at room temperature, 1 ml of methanol was added and after 1 hour the solution was evaporated to dryness. The residue was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate, and the organic phase was dried, filtered and evaporated. An oily material is obtained which is a mixture of the product and the furanone starting material. The resulting material was used in the next step without purification.

Step 6: N-r 2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (tert-butyl)

Preparation of dimethylsilyloxy) -5- {2- [3 (S) -N '- (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide is dissolved in 1 ml of DMF. The crude product obtained in Step 5 was treated with 47 mg (0.246 mmol) of EDC, 33 mg (0.246 mmol) of HOBT and 37 mg of 2 (R) -hydroxy-1 (S) -aminoindan. The pH of the solution was adjusted to 8.5-9.0 by addition of triethylamine, and after 18 hours the reaction mixture was evaporated to dryness and the residue was dissolved in 10% aqueous citric acid solution. The solution was washed with ethyl acetate and the organic phase was dried, filtered and evaporated. The resulting oily substance was chromatographed (SiO ₂ ; 30% EtOAc in hexane). The title compound is obtained.

Step 7: N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- {2-

- Preparation of [3 (S) -N '- (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin-1-yl} -pentanamide

The product obtained in Step 6 is dissolved in 1 ml of THF and 1 ml of a 1 molar solution of tetrabutylammonium fluoride in THF is added. After 18 hours at room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 mL). The product was extracted into ethyl acetate. The organic phase was dried, filtered and evaporated. A foam was obtained, which was chromatographed on a preparative chromatography plate (0.5 mL; 5% MeOH in CHCl ₃ ). The title compound is isolated in the usual manner as a solid. Melting point: 105-107 ° C.

Example 5 N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -amino-5- {2- [3 (S) -N ' Preparation of - (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide

Step 1: 5 (S) -r- (tert-Butyldimethylsilyloxy) methyl] -3 (R) -phenylmethyl-N-

Preparation of -BOC-2-pyrrolidinone

To a solution of 1.3 ml of 1 molar lithium hexamethyldisilazide cooled to -78 ° C and 5 ml of THF was added 5 mg of (S) - [(tert-butyldimethylsilyloxy) 400 mg (1.26 mmol)). -methyl] -N-BOC-2-pyrrolidinone and 2 ml THF was added. After 45 minutes, benzyl bromide (0.15 mL, 1.3 mmol) was added and stirring was continued. After 5 hours, the reaction mixture was poured into a separatory funnel containing 30 mL of water and 10% citric acid solution. The aqueous layer was extracted with EtOAc (2 x 30 mL) and washed with brine (50 mL). The organic layer was dried, filtered and evaporated. An oily residue is obtained which is chromatographed (SiO ₂ ; 20% EtOAc in hexane). The product is obtained in the form of an oily substance.

Step 2: Preparation of 5 (S) -Hydroxymethyl-3 (R) -phenylmethyl-2-pyrrolidinone

Containing 5 (S) - [(tert-butyldimethylsilyloxy) methyl] -3 (R) -phenylmethyl-N-BOC-2-pyrrolidinone (130 mg, 0.34 mmol) and acetonitrile (5 mL) to the reaction mixture was added 1 ml of a 48% aqueous solution of hydrogen fluoride. The reaction mixture was kept at room temperature for 3 hours and then evaporated to dryness. The residue was diluted with 30 ml of aqueous 10% sodium bicarbonate solution. The resulting solution was extracted with EtOAc (2 x 30 mL), dried, filtered and evaporated. The crude product was used without further purification.

. · 'I ^:: ··. . · '.

.........

Step 3: Preparation of 5 (S) - (methanesulfonyloxy) methyl-3 (R) -phenylmethyl-2-pyrrolidinone Dissolve the crude product of Step 2 in dichloromethane and cool to 0 ° C. and triethylamine (42 mg, 0.41 mmol) and methanesulfonyl chloride (47 mg, 0.41 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature and stirred at this temperature for 18 hours. The reaction mixture was then diluted with dichloromethane (30 mL) and washed with 10% citric acid (30 mL). The organic phase was dried, filtered and evaporated. The product is obtained in the form of an oily substance.

Step 4: 5 (S) - {2- [3- (S) -N- (tert-Butylcarboxamido) - (4aS, 8aS) - (Decahydroisoquinolin) -yl] methyl} -3 (R) - preparation of phenylmethyl-2-pyrrolidinone

For a solution of 380 mg (1.34 mmol) of 5 (S) - (methanesulfonyloxy) methyl-3 (R) -phenylmethyl-2-pyrrolidinone and 20 ml of isopropanol, 350 mg of potassium carbonate and 360 mg of N -tert-butyl (4aS, 8aS) - (decahydroisoquinoline) -3 (S) -carboxamide is added. The resulting reaction mixture was heated at 85 ° C for 18 hours. The reaction mixture was cooled, filtered through celite and evaporated to dryness. The residue was dissolved in water and the aqueous solution was extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried, filtered and evaporated. The residue was chromatographed [SiO ₂ ; EtOAc / hexane (50:50)]. The product is obtained in the form of an oily substance.

Step 5: 5 (S) - {2- [3- (S) -N ^, - (tert-Butylcarboxamido) - (4aS, 8aS) - (Decahydro-isoquinoline) -ylmethyl] -3 (R) - preparation of phenylmethyl-N-BOC-2-pyrrolidinone

To a solution of the product of Step 4 (260 mg, 0.611 mmol) in dichloromethane (10 mL) was added dimethylaminopyridine (74 mg, 0.6 mmol) and BOC anhydride (133 mg, 0.61 mmol). After 18 hours at room temperature, 30 ml of dichloromethane are added.

The organic layer was washed with 30 mL of 10% citric acid solution and 30 mL of brine, dried, filtered and evaporated. An oily substance is obtained which is chromatographed (SiO ₂ ; 40% EtOAc in hexane). The title compound is obtained.

Step 6: 5- (2-r 3 (S) -N '- (tert-Butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -4 (S) - [(r, r) - Preparation of (dimethylethoxycarbonyl) amino] -2 (R) -phenylmethylpentanoic acid

The product of Step 5 (260 mg, 0.495 mmol) was dissolved in dimethoxyethane (3 mL) and treated with 1M aqueous lithium hydroxide (1.5 mL, 1.5 mmol). The reaction mixture was allowed to stand for 2 hours and then evaporated to dryness. The residue was dissolved in saturated aqueous ammonium chloride solution and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic phase was dried, filtered and evaporated.

Step 7: N-R 1 R 1 -Hydroxy-1 (S) -indanyl-2 (R) -phenylmethyl-4 (S) - [(1 ', 1') - (Dimethylethoxycarbonyl) - amino] -5- {2- [3- (S) -N '- (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin-1-yl} -pentanamide

The crude product acid from step 6 (260 mg, 0.49 mmol) was dissolved in dichloromethane and then treated with EDC (94 mg, 0.49 mmol), HOBT (66 mg, 0.49 mmol) and 73 mg (0.49 mmol). 2 (R) -hydroxy-1 (S) -aminoindan (0.49 mmol) was added. The pH of the resulting reaction mixture was quenched by addition of triethylamine

Set to 8.5-9.0. After 5 hours at room temperature, dichloromethane (50 mL) was added. The organic layer was washed with saturated aqueous ammonium chloride solution, dried, filtered and evaporated. The residue is chromatographed. The title compound is obtained as a foam.

Step 8: N- [2 (R) -Hydroxy-1 (S) -indanyl-1-2 (R) -phenylmethyl-4 (S) -hydroxy] -5- {2- [3 (S) -N ' - (tert-Butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide

A solution of the product of Step 7 (180 mg, 0.28 mmol) and dichloromethane (5 mL) was cooled to 0 ° C and then trifluoroacetic acid (1 mL) was added. The reaction mixture was allowed to stand for 4 hours and then evaporated to dryness. The residue was dissolved in dichloromethane (50 mL) and the solution was washed with 10% aqueous sodium bicarbonate. The organic layer was dried, filtered and evaporated. A solid is obtained which is chromatographed (SiO ₂ ; CH ₂ Cl ₂ containing 7% MeOH). M.p. 92-95 ° C.

Example 6 N-F2 (R) -Hydroxy-1 (S) -indanyl-2 (R) -phenylmethyl-4 (S) -hydroxy-5-1H-carbobenzyloxy-2 (S) -N Preparation of tert-butylcarboxamido-piperazinyl-11-pentanamide

Following the procedure of Example 1, but substituting N-tert-butyl-4 (S) -phenoxy-L-prolinamide in Step 9, N-tert-butyl-4-CBZ-piperazine-2 (S) -carboxamide applying the title compound.

Example 7 N '- [N- (2-Pyridyl) -valyl-1-2 (R) -phenylmethyl-4 (S) -hydroxy-5-f 2- [3 (S) - (N'-tert. butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin-1-yl} -pentanamide

Following the procedure of Example 4, but using Step 2 instead of 2 (R) -hydroxy-1 (S) -aminoindan, the title compound is obtained.

Example 8 N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5- [2 (S) - (N * -tert) -butyl-3-phenylpropionamide) amino-1-pentanamide

Following the procedure of Example 1, but using Step 9 instead of N'-tert-butyl-4 (S) -phenoxy-L-prolinamide, N-tert-butylphenylalaninamide was obtained to give the title compound.

Example 9 N- [4- (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl] -2 (R) -phenylmethyl-4 (S) -hydroxy-5-f-2. Preparation of [3 (S) - (N'-tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin-1-yl] pentanamide

Step 1: N-r 4 (S) -3,4-Dihydro-1H-benzothiopyranyl) -2 (R) -phenylmethyl-4 (S) -

Preparation of -hydroxy-5- {2- [3- (S) - (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolinyl] -pentanamide

Following the procedure of Example 4, but substituting 4 (S) -amino-3,4-dihydro-1H-benzothiopyran instead of 2 (R) -hydroxy-1 (S) -aminoindan used in Step 6, The title compound is obtained.

Step 2: N-4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl) -2 (R) -phenyl-

Preparation of methyl 4 (S) -hydroxy-5- {2- [3- (S) - (tert-butylcarboxamido) (4aS, 8aS) -decahydroisoquinolin-1-yl] -pentanamide

The compound obtained in Step 1 was dissolved in methanol / water (1: 1). To the solution was added 10 molar equivalents of OXONE and the resulting reaction mixture was stirred at room temperature. At the end of the reaction, the reaction mixture was evaporated to dryness and water was added to the residue. The aqueous solution was extracted with ethyl acetate, then dried, filtered and evaporated. The title compound is obtained.

Example 10 N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl) -2 (R) -phenylmethyl-4 (S) -hydroxy-5- (1) Preparation of -4-Carbobenzyloxy-2 (S) -N'-tert-butylcarboxamido) piperazinylH-pentanamide

Step 1: Dihydro-5 (S) - {1- (4-carbobenzyloxy-2 (S) -N ^, - (tert-butylcarboxamido) piperazinyl] methyl} -3 (R) -phenyl Preparation of methyl-3 (2H) -furanone

Following the procedure of Example 4, but in step 4, instead of N'-tert-butyl (4aS, 8aS) - (decahydroisoquinoline) -3 (S) -carboxamide, 4-carbobenzyloxy-2 (S) -N Using tert-butylcarboxamido-piperazine, the title compound is prepared.

Step 2: 2 (R) -phenylmethyl-4 (S) - (tert-butyldimethylsilyloxy) -5-yl-4-carbobenzyloxy-2 (S) -N ' - (tert-Butylcarboxamido) piperazinyl]} pentanoic acid

Following the procedure of Example 4, but in step 5, the dihydro-5 (S) - {2- [3 (S) -N '- (tert-butylcarboxamido) - (4aS, 8aS) - (decahydro) -isoquinolin-1-yl] methyl} -3 (R) -phenylmethyl-3 (2H) -furanone instead of dihydro-5 (S) - {1- [4-carbobenzyloxy-2 (S) -N ' - (tert-butylcarboxamido) piperazinyl] methyl} -3 (R) -phenylmethyl-3 (2H) -furanone gives the title compound.

Step 3: N- [4 (S) -3,4-Dihydro-1H-benzothiopyranyl) -2 (R) -phenylmethyl-4 (S) -

Preparation of - (tert-butyldimethylsilyloxy) -5- {1- [4-carbobenzyloxy-2 (S) -N '- (tert-butylcarboxamido) -piperazinyl] -pentanamide in ml DMF dissolving the crude product 2 (R) -phenylmethyl-4 (S) - (tert-butyldimethylsilyloxy) -5- {1- [4-carbobenzyloxy-2 (S) -N ' - (tert-butylcarboxamido) piperazinyl]} pentanoic acid, as well as 1 molar equivalent of EDC, 1 molar equivalent of HOBT and 1 molar equivalent of 4 (S) -amino-3,4-dihydro-1H-benzothiopyran. The resulting solution was adjusted to pH with triethylamine

Set between 8.5 and 9.0. The reaction mixture was allowed to stand for 18 hours and then evaporated to dryness. The residue was dissolved in 10% aqueous citric acid solution and the aqueous phase was washed with ethyl acetate. The organic phase was dried, filtered and evaporated. The resulting residue is chromatographed. The title compound is obtained.

Step 4: N-r (S) -3,4-Dihydro-1H-benzothiopyranyl) -2 (R) -phenylmethyl-4 (S) -

hydroxyethyl] -5- | Preparation of 1- [4-carbobenzyloxy-2 (S) - (tert-butylcarboxamido) piperazinyl]} pentanamide

The product of Step 3 was dissolved in THF (1 mL) and treated with 1 mL of a 1 M solution of tetrabutylammonium fluoride in THF. The reaction mixture was allowed to stand at room temperature for 18 hours and then diluted with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous solution was extracted with ethyl acetate. The organic phase was dried, filtered and evaporated. The residue is chromatographed. The title compound is obtained.

Step 5: N- [4 (S) -3,4-Dihydro-1H-2,2-dioxobenzothiopyranyl) -2 (R) -phenyl-

Preparation of methyl 4 (S) -hydroxy] -5- {1- [4-carbobenzyloxy-2 (S) -N '- (tert-butylcarboxamido] piperazinyl] -1-pentanamide

The compound obtained in Step 4 was dissolved in methanol / water (1: 1). To the solution was added 10 molar equivalents of OXONE and the resulting reaction mixture was stirred at room temperature. At the end of the reaction, the reaction mixture was evaporated to dryness. Water was added to the residue and the aqueous solution was extracted with ethyl acetate. The organic solution was dried, filtered and evaporated. The title compound is obtained.

Example 11

N-t2 (R) -hydroxy-l (S) -indanyl] -2 (R) -íf4 - [(2-hydroxy) ethoxy] phenyl] -4 (S) -hydroxy-5-r2- Preparation of 13 (S) -N '- (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide

Step 1: N-R 2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -R 4 - (2-allyloxy) phenyl] methyl} -

Preparation of -4 (S) -hydroxy] -5- {2- [3 (S) - (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [4- (hydroxyphenyl) methyl] -4 (S) -hydroxy] -5- {2- [3 (S) - (tert-Butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide is added with 6 molar equivalents of allyl bromide and 6 molar equivalents of cesium carbonate. The resulting reaction mixture was heated to 90 ° C. The precipitate was filtered off, the dioxane was evaporated to dryness to remove dioxane, and the residue was diluted with water and washed with ethyl acetate. The organic phase was dried, filtered and evaporated. The title compound is obtained.

Step 2: N- [2 (R) -Hydroxy-1 (S) -indanyl-2 (R) - {4-r (2-hydroxy) -ethoxyl-phenyl) -methyl] -4 (S) ) -hydroxy] -5-f2- [3 (S) - (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinoline] -1B-pentanamide

The product of Step 1 is dissolved in methanol and 1 molar equivalent of p-toluenesulfonic acid is added. The reaction mixture was cooled to -78 ° C. Ozone was bubbled through the reaction mixture until the reaction mixture was blue. The flask was then purged with nitrogen to remove excess ozone, and an excess of sodium borohydride was added to the reaction mixture. The reaction mixture was then warmed to room temperature and saturated aqueous sodium bicarbonate was added. Methanol was removed from the reaction mixture on a rotary evaporator and the aqueous residue was washed with ethyl acetate, the organic phase was dried, filtered and evaporated. The title compound is obtained.

Example 12 N-r 2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -r (4-r (2-hydroxy) -ethoxy-1-phenyl) -methyl] -4 (S) -hydroxy Preparation of -5- {1- [4-Carbobenzyloxy-2 (S) -N '- (tert-butylcarboxamidol-piperazinyl]} - pentanamide

Following the procedure of Example 11 but using N- [2 (R) -hydroxy-1 (S) -indanyl] -2 (R) - [(4-hydroxyphenyl) methyl] -4 (S) -hydroxy] -5- {2- [3 (S) - (tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl} -pentanamide instead of N- [2 (R) -hydroxy-1 (S) ) -indanyl] -2 (R) - [(4-hydroxyphenyl) methyl] -4 (S) -hydroxy] -5- {1- [4-carbobenzyloxy-2 (S) - (tert-) butylcarboxamido) piperazinyl] pentanamide to give the title compound.

Example 13

N-r 2 (R) -hydroxy-1 (S) -indanyl-1-2 (R) - [2 - [(4-morpholinyl) ethoxy] phenyl} methyl] -4 (S) -hydroxy-5 Preparation of 2- [3- (S) -N'-tert-butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolin] -yl-1-pentanamide

N- [2 (R) -hydroxy-l (S) -indanyl] -2 (R) - [(4-hydroxyphenyl) methyl] -4 (S) -hydroxy-5- {2- [3- ( S) -N'-tert-Butylcarboxamido) - (4aS, 8aS) -decahydroisoquinolinyl-yl} -pentanamide was dissolved in dioxane, and 6 molar equivalents of chloroethylmorpholine and 6 molar equivalents of cesium carbonate were added. The resulting reaction mixture was heated to 90 ° C. At the end of the reaction, the precipitate was filtered off, the dioxane was evaporated to dryness and the residue was diluted with water and washed with ethyl acetate. The organic phase was dried, filtered and evaporated. The title compound is obtained.

Example 14

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [2- (2- (4-morpholinyl) ethoxy] -phenylmethyl) -4 (S) -hydroxy- Preparation of 5- [1- (4-Carbobenzyloxy-2 (S) -N '- (tert-butylcarboxamido) piperazinyl]) pentanamide

N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) - [(4-hydroxyphenyl) methyl] -4 (S) -hydroxy-5- {1- [4- Carbobenzyloxy-2 (S) - (tert-butylcarboxamido) piperazin-9-yl]} pentanamide was dissolved in dioxane, and 6 molar equivalents of chloroethylmorpholine and 6 molar equivalents of cesium carbonate were added. The resulting reaction mixture was heated to 90 ° C. At the end of the reaction, the precipitate was filtered off, the dioxane was evaporated to dryness and the residue was diluted with water and washed with ethyl acetate. The organic phase was dried, filtered and evaporated. The title compound is obtained.

Example 15 N- [2 (R) -Hydroxy-1 (S) -indanyl-1-2 (R) -phenylmethyl-4 (S) -hydroxy-5- [1- [4- (3-pyridyl) methyl] ) Preparation of -2 (S) -N '- (tert-butylcarboxamido) piperazinyl] [pentanamide

Step 1: Preparation of Dihydro-5 (S) - [(trifluoromethanesulfonyl) oxymethyl] -3 (R) -phenylmethyl-3 (2H) -furanone

A solution of 18.4 g (89.2 mmol) of dihydro-5 (S) - (hydroxymethyl) -3 (R) -phenylmethyl-3 (2H) -furanone and 350 ml of dichloromethane was added at 0 ° C. After cooling, 2,6-lutidine (13.51 mL, 115.98 mmol) was added followed by dropwise addition of trifluoromethanesulfonic anhydride (16.51 mL, 98.1 mmol). After 1.5 hours at 0 ° C, the reaction mixture was poured into 300 ml of ice / brine and stirred for 0.5 hours. The aqueous layer was then extracted with dichloromethane (3 x 150 mL), and the organic layer was washed with 10 mL of 10% hydrochloric acid (2 x 75 mL), saturated aqueous sodium bicarbonate (100 mL), and water (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated. The solid residue was purified by flash chromatography [120 x 150 mm column, gradient elution with hexane / EtOAc (4: 1) → 3: 1) to give the title compound, m.p. 53-54 ° C.

Step 2: Preparation of 4- (1,1-dimethylethyl) -1- (phenylmethyl) -1,2 (S), 4-piperazine tricarboxylate

The title compound was prepared according to the procedure described in Bigge, C. F .; Hays, S. J.; Novak, P. M.; Drummond, J.

T .; Johnson, G.; Bobovski, TP: Tetrahedron Lett., 1989, 30, 5193, using 2 (S) -piperazine carboxylic acid as starting material (see Felder, E .; Maffei, S.; Pietra, S.; Pitre, D: Helv. Chim. Acta, 117, 888 (1960).

Step 3: N-tert-Butyl-4- (1,1-dimethyl-ethoxycarbonylamino) -1- (phenylmethyl)

-carbonylamino) -piperazine-2 (S) -carboxamide

4- (1,1-Dimethylethyl) -1- (phenylmethyl) -1,2 (S), 4-piperazine tricarboxylate (9.90 g, 27.16 mmol) was dissolved in DMF (75 mL). the solution was cooled to 0 ° C and 5.73 g (29.88 mmol) EDC, 4.03 g (29.88 mmol) HOBT, 3.14 mL (29.88 mmol) tert-butyl amine and finally triethylamine (4.16 mL, 29.88 mmol). The resulting mixture was stirred for 18 hours and then reduced to half volume. The reaction mixture was diluted with EtOAc (600 mL) and washed with 10% HCl solution (2 x 75 mL), saturated sodium bicarbonate solution (1 x 75 mL), water (3 x 75 mL), and brine (1 x 50 mL). The aqueous phase was dried over magnesium sulfate and evaporated. The resulting solid was triturated with EtOAc / hexane (1: 2) and filtered. The title compound is obtained as a white solid. 134-135 ° C.

Step 4: N-tert-Butyl-4- (1,1-dimethyl-ethoxycarbonyl-amino) -piperazine-2 (S) -

-Carboxamide

N-tert-butyl 4- (1,1-dimethylethoxycarbonylamino) -1- (phenylmethylcarbonylamino) -piperazine-2 (S) (1.20 g, 2.86 mmol) 15 ml of methanol were added to the reaction mixture containing 1.1 g (0.086 mmol) of 10% palladium-on-carbon. Hydrogen was added to the reaction vessel and the reaction mixture was stirred for 2 hours. The reaction mixture was then filtered through celite and washed with ethanol. The solvent was removed in vacuo. The title compound is obtained as a foam.

1 H-NMR (300 MHz, CDCl 3) δ: 6.65 (broad r, 1H), 4.10 (m, 1H), 3.81 (broad r, 1H), 3.21 (dd, J = 18 and 7 Hz, 1H), 3.02-2.70 (m, 4H), 2.10-2.0 (broad r, 1H), 1.50 (s, 9H), 1.41 (s, 9H) ).

Step 5: Dihydro-5 (S) - [4- (1,1-dimethylethoxycarbonylamino) -2- (S) -N- (tert-butylcarboxamido) -piperazinyl] -1-methyl} -3 Preparation of (R) -phenylmethyl-3 (2H) -furanone

22.40 g (0.0662 mol) of dihydro-5 (S) - [(trifluoromethanesulfonyl) oxymethyl] -3 (R) -phenylmethyl-3 (2H) -furanone (m.p. (186 g, 0.063 mol) of n-tert-butyl-4- (1,1-dimethylethoxycarbonylamino) piperazine-2 (S) -carboxamide was dissolved in 180 ml of isopropanol and then added to the solution.

11.53 mL (0.0662 mol) of Ν, Ν-diisopropylethylamine was added. After 2.5 hours, another 1.2 g of dihydro-5 (S) - [(trifluoromethanesulfonyl) oxymethyl] -3 (R) -phenylmethyl-3 (2H) -furanone was added. TLC showed the reaction to be complete after 3.5 hours and then concentrated. A thick oily substance was obtained which was triturated with 200 mL of EtOAc / hexane (1: 2). A white solid is obtained which is filtered off and discarded. The oily material was purified by flash chromatography [120 x 150 mm column, elution gradient EtOAc / hexane (1: 1) -> (2: 1) -> (3: 1) -> as EtOAc]. The title compound is obtained.

'H NMR (400 MHz, _CDC1?) Δ: 7.34-7.17 (m, 5H), 6.31 (br s, 1H), 4.38 (br m, 1H), 3,96- 3.92 (m, 1H), 3.79 (broad m, 1H), 3.16 (dd, J = 13.6 and 4.4 Hz, 1H), 3.08-2.99 (m, 3H). ), 2.90-2.82 (m, 1H), 2.80 (dd, J = 13.5 and 8.9 Hz, 1H), 2.78 (m, 1H), 2.67-2, 61 (m, 1H), 2.58-2.49 (m, 1H), 2.38-2.32 (m, 1H), 2.32-2.04 (m, 1H), 1.99-. 1.92 (m, 1H), 1.45 (s, 9H), 1.29 (s, 9H).

Step 6: 2 (R) -Phenylmethyl-4 (S) - (tert-butyl-dimethyl-silyloxy) -5-yl- [4- (1,1-dimethyl-ethoxycarbonyl-amino) ) Preparation of n-2 (S) -N- (tert-butylcarboxamido) piperazinyl-1-pentanamide

25.50 g (52.50 mmol) of dihydro-5 (S) - [4- (1,1-dimethylethoxycarbonylamino)] - 2 (S) -N- (tert-butylcarboxamide) - piperazinyl] -methyl} -3 (R) -phenylmethyl-3 (2H) -furanone was dissolved in DME (120 mL), cooled to 0 ° C, water (60 mL) and 1.512 g (63.01 mmol). a solution containing lithium hydroxide is added. After 0.5 h, the reaction was quenched by the addition of 10% hydrochloric acid to pH 6, and the reaction mixture was concentrated in vacuo. The residue was dissolved in water (50 mL) and extracted with EtOAc (4 x 75 mL). The organic layer was washed with water (1 x 20 mL) and brine (1 x 20 mL). The aqueous layer was extracted with EtOAc (2 x 75 mL). The combined organic layers were dried over magnesium sulfate and evaporated. A yellow solid is obtained. The crude product was dissolved in DMF (100 mL) and imidazole (17.87 g, 0.262 mol) was added. The resulting reaction mixture was cooled to 0 ° C and 31.50 g (0.21 mol) of tert-butyldimethylsilyl chloride was added. The resulting reaction mixture was stirred at 0 ° C for 1 hour and then warmed to room temperature. The reaction mixture was maintained at this temperature for 20 hours and quenched with methanol (10 mL). The reaction volume is then reduced to half. To the reaction mixture was added 100 mL of pH 7 buffered water and the aqueous layer was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with 2 x 50 mL 10% w / w hydrochloric acid, 3 x 75 mL water and 1 x 50 mL brine. The organic phase was dried over magnesium sulfate and evaporated. The title compound is obtained which is used directly in the next step.

Step 7: N- (2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (tert-butyldimethylsilyloxy) - Preparation of 5- {1- (4- (1,1-Dimethyl-ethoxycarbonylamino)]} -2 (S) -N- (tert-butylcarboxamido) -piperazinyl-1-pentanamide

The crude product from Step 6 (27.0 g, 0.0446 mol) was dissolved in DMF (180 mL), cooled to 0 ° C, and EDC (8.98 g, 0.0468 mol), 6.32 g. HOBt (0.0468 mole) and amino hydroxyindan (7.31 g, 0.049 mole) were added. To the reaction mixture was added triethylamine (6.52 mL, 0.0468 mole) and the resulting mixture was stirred at 0 ° C for 2 hours and then at room temperature for 16 hours. The reaction was quenched by addition of 500 mL of EtOAc. The organic layer was washed with 2 x 100 mL of 10% hydrochloric acid, 1 x 100 mL of saturated sodium bicarbonate solution, 3 x 150 mL of water, and 1 x 75 mL of brine. The organic layer was dried over magnesium sulfate and evaporated. The title compound is obtained in the form of a white foam.

1 H-NMR (400 MHz, CPC ₁₃ ) δ: 7.4-7.17 (m, 9H), 6.51 (br s, 1H), 5.79 (br s, 1H), 5.23 ( m, 1H), 4.23 (br s, 1H), 4.06 (m, 1H), 3.96-3.84 (m, 2H), 3.07-2.78 (m, 8H), 3.65 (dd, J = 9.6 and 4.1 Hz, 1H),

2.56-2.44 (m, 2H), 2.29 (dd, J = 12.0 and 4.5 Hz, 1H), 2.17-2.09 (m, 1H), 1.79 ( broad s, 1H), 1.44 (s, 9H), 1.35 (s, 9H), 1.10 (s, 1H), 0.84 (s, 9H), 0.12 (s, 3H) , 0.08 (s, 3H).

Step 8: N- [2 (R) -Hydroxy-1 (S) -indanyl-2 (R) -phenylmethyl-4 (S) - (hydroxy) -5-

- (1- (4- (1,1-Dimethyl-ethoxycarbonylamino))} -2 (S) -N- (tert-butylcarboxamido) piperazinylpentanamide

32.20 g (0.0437 mol) of N- [2 (R) -hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (t-butyldimethylsilyl) oxy) -5- {1 - (4- ^{(1,1-dimethyl-ethoxycarbonyl-amino)]}} - 2 (S) -N- (tert-butyl-carboxamido) -piperazinyl] pentanamide 437 ml Tetrabutylammonium fluoride (0.437 mol) (1.0 M in THF, Ald rich) was added and the resulting mixture was stirred for 18 hours, then concentrated to 200 mL and then diluted with 700 mL of EtOAc. The solution was washed with water (2 x 100 mL), brine (1 x 50 mL), and the aqueous layers were back-extracted with EtOAc (2 x 200 mL), the combined organic layers were dried over magnesium sulfate and evaporated. x 150 mm column, gradient elution, CH ₂ Cl ₂ : NH ₃ saturated with CHCl ₃ : methanol (1% to 1.5% by volume> 2% methanol). of the title compound as a white foam .

1 H-NMR (400 MHz, CPC ₁₃ ) δ: 7.31-7.11 (m, 9H), 6.41 (bs, 1H), 6.23 (d, J = 8.6 Hz, 1H ), 5.25 (dd, J = 8.6 and 4.7 Hz, 1H), 4.21 (m, 1H), 3.83-3.82 (m, 2H), 3.78-3, 61 (m, 2H), 3.22-3.19 (m, 2H), 3.03-2.78 (m, 8H), 2.62-2.58 (m, 1H), 2.41-. 2.35 (m, 2H), 2.04-2.02 (m, 1H),

1.57-1.50 (m, 1H), 1.45 (s, 9H), 1.32 (s, 9H).

Step 9: N- [2 (R) -Hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (hydroxy) -5-111-r 2 (S) - Preparation of N- (tert-butylcarboxamido) piperazinyl]} pentanamide

21.15 g (0.034 mol) of N- [2 (R) -hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (hydroxy) -5- {1- [ 4- (1,1-Dimethyl-ethoxycarbonylamino)]} -2 (S) -N- (tert-butylcarboxamido) -piperazinyl] -pentanamide was dissolved in 350 mL of dichloromethane and the solution was heated to 0 ° C. cool to temperature. To the solution was added 22.43 ml (0.204 mol) of 2,6-lutidine followed by 32.85 ml (0.170 mol) of trimethylsilyl triphthalate in 5 minutes. After 0.5 h, the reaction was quenched by the addition of 80 mL of 10% hydrochloric acid and the mixture was stirred for 0.5 h. Saturated aqueous sodium bicarbonate solution (100 mL) was added to the reaction mixture followed by solid sodium bicarbonate to pH = 8. The aqueous phase was extracted with EtOAc (4 x 100 mL), and the combined organic layer was washed with water (1 x 50 mL) and brine (1 x 75 mL). The carbon phase was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (120 x 150 mm column, gradient elution with CH ₂ Cl ₂ : NH ₃ saturated CHCl ₃ : methanol with methanol content of 2% by volume to> 4% by volume). > 5 vol% -> 6 vol% -> 10 vol%). The title compound is obtained in the form of a white foam.

1 H-NMR (400 MHz, CPC ₁₃ ) δ: 7.53 (s, 1H), 7.29-7.09 (m, 9H), 6.52 (d, J = 8.3 Hz, 1H). , 5.24 (dd, J = 8.2 and 4.9 Hz, 1H), 4.23 (dd, J = 4.7 and 4.03 Hz, 1H), 4.25-4.00 (broad s, 1H), 3.83-3.81 (m, 1H), 3.03-2.88 (m, 4H), 2.82-2.73 (m, 7H), 2.50-1. 60 (bs, 2H), 2.45 (d, J = 6.2 Hz, 2H), 2.32-2.29 (m, 1H), 1.98 (m, 1H), 1.51 ( m, 1H), 1.33 (s, 9H).

Step 10: N- [2 (R) -Hydroxy-1 (S) -indanyl-1-2 (R) -phenylmethyl-4 (S) - (hydroxy) -5-

Preparation of -11- [4- (3-pyridylmethyl) -2 (S) -N ^, - (tert-butylcarboxamido) piperazinyl]} pentanamide

10.0 g (0.019 mol) of N- [2 (R) -hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (hydroxy) -5- {1- [ 2 (S) -N- (tert-Butylcarboxamido) piperazinyl]} pentanamide and 3.45 g (0.021 mol) of 3-picolyl chloride are dissolved in 40 ml of DMF and then 5.85 ml (0.042 mol) of mole) of triethylamine was added. After 3 hours, an additional 0.313 g of 3-picolyl chloride was added to the reaction mixture. After an additional 2 hours, the reaction mixture was diluted with EtOAc (400 mL) and washed with water (3 x 75 mL) and brine (1 x 100 mL). The organic phase was dried over magnesium sulfate and evaporated. The residue was triturated with 30 mL of EtOAc. The resulting white precipitate was filtered and recrystallized from EtOAc. The title compound is obtained. Melting point: 167.5-168 ° C.

Example 16

Following the procedure of Example 15 but using N- [2 (R) -hydroxy-1 (S) -indanyl] -2 (R) -phenylmethyl-4 (S) - (hydroxy) -5- {1 - [2 (S) -N '- (tert-butyl kar86

boxamido) -piperazinyl]} -pentanamide using compound (i) and a

Using the alkylating agent (ii) instead of the 3-picolyl chloride used in Step 10, the following compounds of formula (iii) and the following substituents R ¹ and X were prepared.

R ¹ -X ii

iii

R ¹

Ο k ^ / N ^ CH ₂ Ο <^ n ^, ch ₂ -

X

cl

I

cl

cl

cl

CH ₃ O (CH ₂ CH ₂ O) ₂ -CH ₂ CH ₂ -

Cl * ··· ♦ · ·· * · »· · · * · · ♦ *» * · «·« · «·

Cl * · e · · * 9 · ·· »* • · ·» ♦ · · »·« «···« ·

Cl φ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 17 Preparation of Dihydro-5 (S) - (tert-butyldimethylsilyloxymethyl) -3 (2H) -furanone

Dihydro-5 (S) -hydroxymethyl-2 (3H) -furanone (3.00 g, 25.8 mmol) was dissolved in dichloromethane (25 mL) followed by imidazole (3.51 g, 51.6 mmol). and 4.67 g (31.0 mmol) of tert-butyldimethylsilyl chloride are added. The resulting mixture was stirred at room temperature for 8 hours and quenched with methanol (2 mL). The reaction mixture was evaporated and the resulting oil was diluted with 150 ml of diethyl ether. The organic solution was washed with 2 x 10 mL of 5% hydrochloric acid, 1 x 10 mL of saturated sodium bicarbonate, 1 x 10 mL of water and 1 x 10 mL of brine. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (column 40 x 150 mm, gradient elution, hexane / ethyl acetate (5: 1) → 4: 1). The title compound is obtained as a clear oily substance.

1 H-NMR (300 MHz, CDCl 3 δ: 4.68-4.60 (m, 1H), 3.89 (dd, J = 3.3 and 11.3 Hz, 1H), 3.71 (dd, J = 3.2 and 5411.3 Hz, 1H), 2.71-2.45 (m, 2H), 2.35-2.16 (m, 2H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).

The examples described are intended to illustrate the invention and it will be understood that standard variations, adaptations, or modifications of the disclosed methods are within the scope of the invention.

PATENT CLAIMS

Claims (5)

PATENT CLAIMS A combination of a compound of formula (J), or a pharmaceutically acceptable salt thereof, and any one of AZT or ddl or ddC. Pharmaceutical compositions, characterized in that one A combination according to claim 1 and a pharmaceutically acceptable carrier. Pharmaceutical compositions according to claim 2 for use in the treatment of AIDS, the prevention of HIV infection, the treatment of HIV infection or the inhibition of HIV. A combination according to claim 1 for use in the treatment of AIDS, the prevention of HIV infection, the treatment of HIV infection, or the inhibition of HIV. Use of a combination according to claim 1 for the manufacture of a medicament for the treatment of AIDS, the prevention of HIV infection, the treatment of HIV infection or the inhibition of HIV. Authorized representative: dr. ValyonnéjT. Elvira's patent attorney